Stem cells head to the clinic: treatments for cancer, diabetes and Parkinsons disease could soon be here  Nature.com

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Sumitomo Chemical and Sumitomo Pharma to Establish Regenerative Medicine and Cell Therapy Joint Venture  

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Exclusive: Cell therapy startup Shinobi adds Borges as science chief, Katz as top medical officer  Endpoints News

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Shinobi Strengthens Leadership to Propel Scalable Immune-Evasive Cell Therapies to the Clinic  The Eastern Progress Online

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BrightPath Bio and Cellistic Announces Process Development and Manufacturing Collaboration for Phase 1 Clinical Trial of iPSC-derived BCMA CAR-iNKT cell  Via Ritzau

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Abstract

Induced pluripotent stem cells (iPSCs) are a new type of pluripotent cellsthat can be obtained by reprogramming animal and human differentiated cells. In this review,issues related to the nature of iPSCs are discussed and different methods ofiPSC production are described. We particularly focused on methods of iPSC production withoutthe genetic modification of the cell genome and with means for increasing the iPSC productionefficiency. The possibility and issues related to the safety of iPSC use in cell replacementtherapy of human diseases and a study of new medicines are considered.

Keywords: induced pluripotent stem cells, directed stem cell differentiation, cell replacement therapy

Pluripotent stem cells are a unique model for studying a variety of processes that occur inthe early development of mammals and a promising tool in cell therapy of human diseases. Theunique nature of these cells lies in their capability, when cultured, for unlimitedselfrenewal and reproduction of all adult cell types in the course of theirdifferentiation [1]. Pluripotency is supported by acomplex system of signaling molecules and gene network that is specific for pluripotent cells.The pivotal position in the hierarchy of genes implicated in the maintenance of pluripotency isoccupied by Oct4, Sox2 , and Nanog genes encodingtranscription factors [2, 3]. The mutual effect of outer signaling molecules and inner factors leads tothe formation of a specific expression pattern, as well as to the epigenome statecharacteristic of stem cells. Both spontaneous and directed differentiations are associatedwith changes in the expression pattern and massive epigenetic transformations, leading totranscriptome and epigenome adjustment to a distinct cell type.

Until recently, embryonic stem cells (ESCs) were the only wellstudied source ofpluripotent stem cells. ESCs are obtained from either the inner cell mass or epiblast ofblastocysts [46]. A series of protocols has been developed for the preparation of variouscell derivatives from human ESCs. However, there are constraints for ESC usein cell replacement therapy. The first constraint is the immune incompatibility between thedonor cells and the recipient, which can result in the rejection of transplanted cells. Thesecond constraint is ethical, because the embryo dies during the isolation of ESCs. The firstproblem can be solved by the somatic cell nuclear transfer into the egg cell and then obtainingthe embryo and ESCs. The nuclear transfer leads to genome reprogramming, in which ovariancytoplasmic factors are implicated. This way of preparing pluripotent cells from certainindividuals was called therapeutic cloning. However, this method is technologyintensive,and the reprogramming yield is very low. Moreover, this approach encounters theabovementioned ethic problem that, in this case, is associated with the generation ofmany human ovarian cells [7].

In 2006, the preparation of pluripotent cells by the ectopic expression of four genes Oct4 , Sox2 , Klf4 , and cMyc in both embryonic and adult murine fibroblasts was first reported[8]. The pluripotent cells derived from somatic ones werecalled induced pluripotent stem cells (iPSCs). Using this set of factors(Oct4, Sox2, Klf4, and cMyc), iPSCs were prepared later from variousdifferentiated mouse [914] and human [1517] cell types. Human iPSCs were obtainedwith a somewhat altered gene set: Oct4 , Sox2 , Nanog , and Lin28 [18].Induced PSCs closely resemble ESCs in a broad spectrum of features. They possess similarmorphologies and growth manners and are equally sensitive to growth factors and signalingmolecules. Like ESCs, iPSCs can differentiate in vitro intoderivatives of all three primary germ layers (ectoderm, mesoderm, and endoderm) and formteratomas following their subcutaneous injection into immunodeficient mice. MurineiPSCs injected into blastocysts are normally included in the development toyield animals with a high degree of chimerism. Moreover, murine iPSCs, wheninjected into tetraploid blastocycts, can develop into a whole organism [19, 20]. Thus, an excellent method thatallows the preparation of pluripotent stem cells from various somatic cell types whilebypassing ethical problems has been uncovered by researchers.

In the first works on murine and human iPSC production, either retro or lentiviralvectors were used for the delivery of Oct4 , Sox2 , Klf4 , and cMyc genes into somatic cells. Theefficiency of transduction with retroviruses is high enough, although it is not the same fordifferent cell types. Retroviral integration into the host genome requires a comparatively highdivision rate, which is characteristic of the relatively narrow spectrum of cultured cells.Moreover, the transcription of retroviral construct under the control of a promoter localizedin 5LTR (long terminal repeat) is terminated when the somatic celltransform switches to the pluripotent state [21]. Thisfeature makes retroviruses attractive in iPSC production. Nevertheless, retroviruses possesssome properties that make iPSCs that are produced using them improper for celltherapy of human diseases. First, retroviral DNA is integrated into the host cell genome. Theintegration occurs randomly; i.e., there are no specific sequences or apparent logic forretroviral integration. The copy number of the exogenous retroviral DNA that is integrated intoa genome may vary to a great extent [15]. Retrovirusesbeing integrated into the cell genome can introduce promoter elements and polyadenylationsignals; they can also interpose coding sequences, thus affecting transcription. Second, sincethe transcription level of exogenous Oct4 , Sox2 , Klf4 , and cMyc in the retroviral constructdecreases with cell transition into the pluripotent state, this can result in a decrease in theefficiency of the stable iPSC line production, because the switch from the exogenous expressionof pluripotency genes to their endogenous expression may not occur. Third, some studies showthat the transcription of transgenes can resume in the cells derived fromiPSCs [22]. The high probability thatthe ectopic Oct4 , Sox2 , Klf4 , and cMyc gene expression will resume makes it impossible to applyiPSCs produced with the use of retroviruses in clinical trials; moreover,these iPSCs are hardly applicable even for fundamental studies onreprogramming and pluripotency principles. Lentiviruses used for iPSC production can also beintegrated into the genome and maintain their transcriptional activity in pluripotent cells.One way to avoid this situation is to use promoters controlled by exogenous substances added tothe culture medium, such as tetracycline and doxycycline, which allows the transgenetranscription to be regulated. iPSCs are already being produced using suchsystems [23].

Another serious problem is the gene set itself that is used for the induction of pluripotency[22]. The ectopic transcription of Oct4 , Sox2 , Klf4 , and cMyc can lead to neoplastic development from cells derived from iPSCs,because the expression of Oct4 , Sox2 , Klf4, and cMyc genes is associated with the development ofmultiple tumors known in oncogenetics [22, 24]. In particular, the overexpression of Oct4 causes murine epithelial cell dysplasia [25],the aberrant expression of Sox2 causes the development of serrated polypsand mucinous colon carcinomas [26], breast tumors arecharacterized by elevated expression of Klf4 [27] , and the improper expression of cMyc is observed in 70% of human cancers [28].Tumor development is oberved in ~50% of murine chimeras obtained through the injection ofretroviral iPSCs into blastocysts, which is very likely associated with thereactivation of exogenous cMyc [29, 30].

Several possible strategies exist for resolving the above-mentioned problems:

The search for a less carcinogenic gene set that is necessary and sufficient for reprogramming;

The minimization of the number of genes required for reprogramming and searching for the nongenetic factors facilitating it;

The search for systems allowing the elimination of the exogenous DNA from the host cell genome after the reprogramming;

The development of delivery protocols for nonintegrated genetic constructs;

The search for ways to reprogram somatic cells using recombinant proteins.

The ectopic expression of cMyc and Klf4 genes isthe most dangerous because of the high probability that malignant tumors will develop [22]. Hence the necessity to find other genes that couldsubstitute cMyc and Klf4 in iPSC production. Ithas been reported that these genes can be successfully substituted by Nanog and Lin28 for reprogramming human somatic cells [18;] . iPSCs were prepared from murine embryonic fibroblastsby the overexpression of Oct4 and Sox2 , as well as the Esrrb gene encoding the murine orphan nuclear receptor beta. It has alreadybeen shown that Esrrb , which acts as a transcription activator of Oct4 , Sox2 , and Nanog , is necessary for theselfrenewal and maintenance of the pluripotency of murine ESCs. Moreover, Esrrb can exert a positive control over Klf4 . Thus, the genes causingelevated carcinogenicity of both iPSCs and their derivatives can besuccessfully replaced with less dangerous ones [31].

The Most Effectively Reprogrammed Cell Lines . Murine and humaniPSCs can be obtained from fibroblasts using the factors Oct4, Sox2, and Klf4,but without cMyc . However, in this case, reprogramming deceleratesand an essential shortcoming of stable iPSC clones is observed [32, 33]. The reduction of a number ofnecessary factors without any decrease in efficiency is possible when iPSCsare produced from murine and human neural stem cells (NSCs) [12, 34, 35]. For instance, iPSCs were produced fromNSCs isolated from adult murine brain using two factors, Oct4 and Klf4, aswell as even Oct4 by itself [12, 34]. Later, human iPSCs were produced by the reprogramming offetal NSCs transduced with a retroviral vector only carrying Oct4 [35] . It is most likely that the irrelevanceof Sox2, Klf4, and cMyc is due to the high endogenous expression level of these genes inNSCs.

Successful reprogramming was also achieved in experiments withother cell lines, in particular, melanocytes of neuroectodermal genesis [36]. Both murine and human melanocytes are characterized by a considerableexpression level of the Sox2 gene, especially at early passages.iPSCs from murine and human melanocytes were produced without the use of Sox2or cMyc. However, the yield of iPSC clones produced from murine melanocytes was lower(0.03% without Sox2 and 0.02% without cMyc) in comparison with that achieved when allfour factors were applied to melanocytes (0.19%) and fibroblasts (0.056%). A decreasedefficiency without Sox2 or cMyc was observed in human melanocyte reprogramming (0.05%with all four factors and 0.01% without either Sox2 or cMyc ). All attempts to obtain stable iPSC clones in the absence of both Sox2 andcMyc were unsuccessful [36]. Thus, theminimization of the number of factors required for iPSC preparation can be achieved by choosingthe proper somatic cell type that most effectively undergoes reprogramming under the action offewer factors, for example, due to the endogenous expression of pluripotencygenes. However, if human iPSCs are necessary, these somatic cellsshould be easily accessible and wellcultured and their method of isolation should be asnoninvasive as possible.

One of these cell types can be adipose stem cells (ASCs). This is aheterogeneous group of multipotent cells which can be relatively easily isolated in largeamounts from adipose tissue following liposuction. Human iPSCs weresuccessfully produced from ASCs with a twofold reprogramming rate and20fold efficiency (0.2%), exceeding those of fibroblasts [37].

However, more accessible resources for the effective production of humaniPSCs are keratinocytes. When compared with fibroblasts, human iPSC productionfrom keratinocytes demonstrated a 100fold greater efficiency and a twofold higherreprogramming rate [38].

It has recently been found that the reprogramming of murine papillary dermal fibroblasts(PDFs) into iPSCs can be highly effective with theoverexpression of only two genes, Oct4 and Klf4 ,inserted into retroviral vectors [39;].PDFs are specialized cells of mesodermal genesis surrounding the stem cells ofhair follicles . One characteristic feature of these cells is the endogenous expression of Sox2 , Klf4 , and cMyc genes,as well as the geneencoding alkaline phosphatase, one of the murine and humanESC markers. PDFs can be easily separated from other celltypes by FACS (fluorescenceactivated cell sorting) using life staining with antibodiesagainst the surface antigens characteristic of one or another cell type. The PDF reprogrammingefficiency with the use of four factors (Oct4, Sox2, Klf4, and cMyc) retroviral vectorsis 1.38%, which is 1,000fold higher than the skin fibroblast reprogramming efficiency inthe same system. Reprogramming PDFs with two factors, Oct4 and Klf4 , yields 0.024%, which is comparable to the efficiency of skinfibroblast reprogramming using all four factors. The efficiency of PDF reprogramming iscomparable with that of NSCs, but PDF isolation is steady and far lessinvasive [39]. It seems likely that human PDF lines arealso usable, and this cell type may appear to be one of the most promising for human iPSCproduction in terms of pharmacological studies and cell replacement therapy. The use of suchcell types undergoing more effective reprogramming, together with methods providing thedelivery of pluripotency genes without the integration of foreign DNA into thehost genome and chemical compounds increasing the reprogramming efficiency and substitutingsome factors required for reprogramming, is particularly relevant.

Chemical Compounds Increasing Cell Reprogramming Efficiency. As was noted above,the minimization of the factors used for reprogramming decreases the efficiency of iPSCproduction. Nonetheless, several recent studies have shown that the use of genetic mechanisms,namely, the initiation of ectopic gene expression, can be substituted by chemical compounds,most of them operating at the epigenetic level. For instance, BIX01294 inhibitinghistone methyltransferase G9a allows murine fibroblast reprogramming using only two factors,Oct4 and Klf4, with a fivefold increased yield of iPSC clones in comparison with the controlexperiment without BIX01294 [40]. BIX01294taken in combination with another compound can increase the reprogramming efficiency even more.In particular, BIX01294 plus BayK8644 elevated the yield of iPCSs 15 times, andBIX01294 plus RG108 elevated it 30 times when only two reprogramming factors, Oct4 andKlf4, were used. RG108 is an inhibitor of DNA methyltransferases, and its role in reprogrammingis apparently in initiating the more rapid and effective demethylation of promoters ofpluripotent cellspecific genes, whereas BayK8644 is an antagonist of Ltypecalcium channels, and its role in reprogramming is not understood very well [40]. However, more considerable results were obtained inreprogramming murine NSCs. The use of BIX01294 allowed a 1.5foldincrease in iPSC production efficiency with two factors, Oct4 and Klf4, in comparison withreprogramming with all four factors. Moreover, BIX01294 can even substitute Oct4 in thereprogramming of NSCs, although the yield is very low [41]. Valproic (2propylvaleric) acid inhibiting histone deacetylases canalso substitute cMyc in reprogramming murine and human fibroblasts. Valproic acid (VPA)increases the reprogramming efficiency of murine fibroblasts 50 times, and human fibroblastsincreases it 1020 times when three factors are used [42, 43]. Other deacetylase inhibitors,such as TSA (trichostatin A) and SAHA (suberoylanilide hyroxamic acid), also increase thereprogramming efficiency. TSA increases the murine fibroblast reprogramming efficiency 15times, and SAHA doubles it when all four factors are used [42]. Besides epigenetic regulators, the substances inhibiting the proteincomponents of signaling pathways implicated in the differentiation of pluripotent cells arealso applicable in the substitution of reprogramming factors. In particular, inhibitors of MEKand GSK3 kinases (PD0325901 and CHIR99021, respectively) benefit the establishment of thecomplete and stable pluripotency of iPSCs produced from murineNSCs using two factors, Oct4 and Klf4 [41, 44].

It has recently been shown that antioxidants can considerably increase the efficiency ofsomatic cell reprogramming. Ascorbic acid (vitamin C) can essentially influence the efficiencyof iPSC production from various murine and human somatic cell types [45]. The transduction of murine embryonic fibroblasts (mEFs) with retrovirusescarrying the Oct4 , Sox2 , and Klf4 genes results in a significant increase in the production level of reactive oxygen species(ROS) compared with that of both control and Efs tranduced with Oct4 , Sox2 , cMyc , and Klf4 . Inturn, the increase in the ROS level causes accelerated aging and apoptosis of the cell, whichshould influence the efficiency of cell reprogramming. By testing several substances possessingantioxidant activity such as vitamin B1, sodium selenite, reduced glutathione, and ascorbicacid, the authors have found that combining these substances increases the yield ofGFPpositive cells in EF reprogramming (the Gfp genewas under the control of the Oct4 gene promoter). The use of individualsubstances has shown that only ascorbate possesses a pronounced capability to increase thelevel of GFPpositive cells, although other substances keep theirROSdecreasing ability. In all likelihood, this feature of ascorbates is not directlyassociated with its antioxidant activity [45]. The scoreof GFPpositive iPSC colonies expressing an alkaline phosphatase hasshown that the efficiency of iPSC production from mEFs with three factors (Oct4, Sox2, andKlf4) can reach 3.8% in the presence of ascorbate. When all four factors (Oct4, Sox2, Klf4, andcMyc) are used together with ascorbate, the efficiency of iPSC production may reach8.75%. A similar increase in the iPSC yield was also observed in the reprogramming of murinebreast fibroblasts; i.e., the effect of vitamin C is not limited by one cell type. Moreover,the effect of vitamin C on the reprogramming efficiency is more profound than that of thedeacetylase inhibitor valproic (2propylvaleric) acid. The mutual effect of ascorbate andvalproate is additive; i.e., these substances have different action mechanisms. Moreover,vitamin C facilitates the transition from preiPSCs to stablepluripotent cells. This feature is akin to the effects of PD0325901 and CHIR99021, which areinhibitors of MEK and GSK3 kinases, respectively. This effect of vitamin C expands to humancells as well [45]. Following the transduction of humanfibroblasts with retroviruses carrying Oct4 , Sox2 , Klf4 , and cMyc and treatment with ascorbate, theauthors prepared iPSCs with efficiencies reaching 6.2%. The reprogrammingefficiency of ASCs under the same conditions reached 7.06%. The mechanism ofthe effect that vitamin C has on the reprogramming efficiency is not known in detail.Nevertheless, the acceleration of cell proliferation was observed at the transitional stage ofreprogramming. The levels of the p53 and p21 proteins decreased in cells treated withascorbate, whereas the DNA repair machinery worked properly [45]. It is interesting that an essential decrease in the efficiency of iPSCproduction has been shown under the action of processes initiated by p53 and p21 [4650].

As was mentioned above, for murine and human iPSC production, both retro andlentiviruses were initially used as delivery vectors for the genes required for cellreprogramming. The main drawback of this method is the uncontrolled integration of viral DNAinto the host cells genome. Several research groups have introduced methods fordelivering pluripotency genes into the recipient cell which either do notintegrate allogenic DNA into the host genome or eliminate exogenous genetic constructs from thegenome.

CreloxP Mediated Recombination. To prepareiPSCs from patients with Parkinsons disease, lentiviruses were used,the proviruses of which can be removed from the genome by Cre recombinase. To do this, the loxP site was introduced into thelentiviral 3LTRregions containing separate reprogramming genesunder the control of the doxycyclineinducible promoter. During viral replication, loxP was duplicated in the 5LTR of the vector. As aresult, the provirus integrated into the genome was flanked with two loxP sites. The inserts were eliminated using the temporary transfection ofiPSCs with a vector expressing Cre recombinase[51].

In another study, murine iPSCs were produced using a plasmid carrying the Oct4 , Sox2 , Klf4I, and cMyc genes in the same reading frame in which individual cDNAs were separatedby sequences encoding 2 peptides, and practically the whole construct was flanked with loxP sites [52]. The use ofthis vector allowed a notable decrease in the number of exogenous DNA inserts in the hostcells genome and, hence, the simplification of their following excision [52]. It has been shown using lentiviruses carrying similarpolycistronic constructs that one copy of transgene providing a high expression level of theexogenous factors Oct4, Sox2, Klf4, and cMyc is sufficient for the reprogramming ofdifferentiated cells into the pluripotent state [53,54].

The drawback of the CreloxP system is the incomplete excisionof integrated sequences; at least the loxP site remains in thegenome, so the risk of insertion mutations remains.

Plasmid Vectors . The application of lentiviruses and plasmids carrying the loxP sites required for the elimination of transgene constructsmodifies, although insignificantly, the host cells genome. One way to avoid this is touse vector systems that generally do not provide for the integration of the whole vector orparts of it into the cells genome. One such system providing a temporary transfectionwith polycistronic plasmid vectors was used for iPSC production from mEFs [29]. A polycistronic plasmid carrying the Oct4 , Sox2 , and Klf4 gene cDNAs, as well as aplasmid expressing cMyc , was transfected into mEFs one, three, five,and seven days after their primary seeding. Fibroblasts were passaged on the ninth day, and theiPSC colonies were selected on the 25th day. Seven out of ten experiments succeeded inproducing GFPpositive colonies (the Gfp gene wasunder the control of the Nanog gene promoter). The iPSCsthat were obtained were similar in their features to murine ESCs and did not contain inserts ofthe used DNA constructs in their genomes. Therefore, it was shown that wholesome murineiPSCs that do not carry transgenes can be reproducibly produced, and that thetemporary overexpression of Oct4 , Sox2 , Klf4 , and cMyc is sufficient for reprogramming. The maindrawback of this method is its low yield. In ten experiments the yield varied from 1 to 29 iPSCcolonies per ten million fibroblasts, whereas up to 1,000 colonies per ten millions wereobtained in the same study using retroviral constructs [29].

Episomal Vectors . Human iPSCs were successfully produced fromskin fibroblasts using single transfection with polycistronic episomal constructs carryingvarious combinations of Oct4 , Sox2 , Nanog , Klf4 , cMyc , Lin28 , and SV40LT genes. These constructs were designed on the basis of theoriP/EBNA1 (EpsteinBarr nuclear antigen1) vector [55]. The oriP/EBNA1 vector contains the IRES2 linker sequence allowing theexpression of several individual cDNAs (encoding the genes required for successfulreprogramming in this case) into one polycistronic mRNA from which several proteins aretranslated. The oriP/EBNA1 vector is also characterized by lowcopy representation in thecells of primates and can be replicated once per cell cycle (hence, it is not rapidlyeliminated, the way common plasmids are). Under nonselective conditions, the plasmid iseliminated at a rate of about 5% per cell cycle [56]. Inthis work, the broad spectrum of the reprogramming factor combinations was tested, resulting inthe best reprogramming efficiency with cotransfection with three episomes containing thefollowing gene sets: Oct4 + Sox2 + Nanog + Klf4 , Oct4 + Sox2 + SV40LT + Klf4 , and cMyc + Lin28 . SV40LT ( SV40 large T gene )neutralizes the possible toxic effect of overexpression [57]. The authors have shown thatwholesome iPSCs possessing all features of pluripotent cells can be producedfollowing the temporary expression of a certain gene combination in human somatic cells withoutthe integration of episomal DNA into the genome. However, as in the case when plasmid vectorsare being used, this way of reprogramming is characterized by low efficiency. In separateexperiments the authors obtained from 3 to 6 stable iPSC colonies per 106transfected fibroblasts [55]. Despite the fact that skinfibroblasts are wellcultured and accessible, the search for other cell types which arerelatively better cultured and more effectively subject themselves to reprogramming throughthis method is very likely required. Another drawback of the given system is that this type ofepisome is unequally maintained in different cell types.

PiggyBacTransposition . One promising system used foriPSC production without any modification of the host genome is based on DNA transposons.Socalled PiggyBac transposons containing2linkered reprogramming genes localized between the 5 and3terminal repeats were used for iPSC production from fibroblasts. The integrationof the given constructs into the genome occurs due to mutual transfection with a plasmidencoding transposase. Following reprogramming due to the temporary expression of transposase,the elimination of inserts from the genome took place [58, 59]. One advantage of the PiggyBac system on CreloxP is that the exogenous DNA iscompletely removed [60].

However, despite the relatively high efficiency of exogenous DNA excision from the genome by PiggyBac transposition, the removal of a large number of transposoncopies is hardly achievable.

Nonintegrating Viral Vectors . Murine iPSCs were successfullyproduced from hepatocytes and fibroblasts using four adenoviral vectors nonintegrating into thegenome and carrying the Oct4 , Sox2 , Klf4 , and cMyc genes. An analysis of the obtainediPSCs has shown that they are similar to murine ESCs in their properties(teratoma formation, gene promoter DNA methylation, and the expression of pluripotent markers),but they do not carry insertions of viral DNA in their genomes [61]. Later, human fibroblastderived iPSCs wereproduced using this method [62].

The authors of this paper cited the postulate that the use of adenoviral vectors allows theproduction of iPSCs, which are suitable for use without the risk of viral oroncogenic activity. Its very low yield (0.00010.001%), the deceleration ofreprogramming, and the probability of tetraploid cell formation are the drawbacks of themethod. Not all cell types are equally sensitive to transduction with adenoviruses.

Another method of gene delivery based on viral vectors was recently employed for theproduction of human iPSCs. The sendaivirus (SeV)based vector wasused in this case [63]. SeV is a singlestrandedRNA virus which does not modify the genome of recipient cells; it seems to be a good vector forthe expression of reprogramming factors. Vectors containing either all pluripotencyfactors or three of them (without ) were used for reprogramming the human fibroblast. The construct based on SeV is eliminatedlater in the course of cell proliferation. It is possible to remove cells with the integratedprovirus via negative selection against the surface HN antigen exposed on the infected cells.The authors postulate that reprogramming technology based on SeV will enable the production ofclinically applicable human iPSCs [63].

Cell Transduction with Recombinant Proteins . Although the methods for iPSCproduction without gene modification of the cells genome (adenoviral vectors, plasmidgene transfer, etc.) are elaborated, the theoretical possibility for exogenous DNA integrationinto the host cells genome still exists. The mutagenic potential of the substances usedpresently for enhancing iPSC production efficiency has not been studied in detail. Fullychecking iPSC genomes for exogenous DNA inserts and other mutations is a difficult task, whichbecomes impossible to solve in bulk culturing of multiple lines. The use of protein factorsdelivered into a differentiated cell instead of exogenous DNA may solve this problem. Tworeports have been published to date in which murine and human iPSCs wereproduced using the recombinant Oct4, Sox2, Klf4, and cMyc proteins [64, 65] . T he methodused to deliver the protein into the cell is based on the ability of peptides enriched withbasic residues (such as arginine and lysine) to penetrate the cells membrane. MurineiPSCs were produced using the recombinant Oct4, Sox2, Klf4, and cMycproteins containing eleven Cterminal arginine residues and expressed in E. coli . The authors succeeded in producing murine iPSCs during four roundsof protein transduction into embryonic fibroblasts [65].However, iPSCs were only produced when the cells were additionally treatedwith 2propylvalerate (the deacetylase inhibitor). The same principle was used for theproduction of human iPSCs, but protein expression was carried out in humanHEK293 cells, and the proteins were expressed with a fragment of nine arginins at the proteinCend. Researchers have succeeded in producing human iPSCs after sixtransduction rounds without any additional treatment [64]. The efficiency of producing human iPSC in this way was 0.001%, which isone order lower than the reprogramming efficiency with retroviruses. Despite some drawbacks,this method is very promising for the production of patientspecificiPSCs.

The first lines of human pluripotent ESCs were produced in 1998 [6]. In line with the obvious fundamental importance of embryonic stem cellstudies with regard to the multiple processes taking place in early embryogenesis, much of theinterest of investigators is associated with the possibility of using ESCs and theirderivatives as models for the pathogenesis of human diseases, new drugs testing, and cellreplacement therapy. Substantial progress is being achieved in studies on directed humanESC differentiation and the possibility of using them to correct degenerativedisorders. Functional cell types, such as motor dopaminergic neurons, cardiomyocytes, andhematopoietic cell progenitors, can be produced as a result of ESCdifferentiation. These cell derivatives, judging from their biochemical and physiologicalproperties, are potentially applicable for the therapy of cardiovascular disorders, nervoussystem diseases, and human hematological disorders [66].Moreover, derivatives produced from ESCs have been successfully used for treating diseasesmodeled on animals. Therefore, bloodcell progenitors produced from ESCs weresuccessfully used for correcting immune deficiency in mice. Visual functions were restored inblind mice using photoreceptors produced from human ESCs, and the normal functioning of thenervous system was restored in rats modeling Parkinsons disease using the dopaminergicneurons produced from human ESCs [6770]. Despite obvious success, the fullscale applicationof ESCs in therapy and the modeling of disorders still carry difficulties, because of thenecessity to create ESC banks corresponding to all HLAhaplotypes, whichis practically unrealistic and hindered by technical and ethical problems.

Induced pluripotent stem cells can become an alternative for ESCs in the area of clinicalapplication of cell replacement therapy and screening for new pharmaceuticals.iPSCs closely resemble ESCs and, at the same time, can be produced in almostunlimited amounts from the differentiated cells of each patient. Despite the fact that thefirst iPSCs were produced relatively recently, work on directed iPSCdifferentiation and the production of patientspecific iPSCs isintensive, and progress in this field is obvious.

Dopamine and motor neurons were produced from human iPSCs by directeddifferentiation in vitro [71, 72]. These types of neurons are damaged in many inherited oracquired human diseases, such as spinal cord injury, Parkinsons disease, spinal muscularatrophy, and amyotrophic lateral sclerosis. Some investigators have succeeded in producingvarious retinal cells from murine and human iPSCs [7375]. HumaniPSCs have been shown to be spontaneously differentiated in vitro into the cells of retinal pigment epithelium [76]. Another group of investigators has demonstrated that treating human andmurine iPSCs with Wnt and Nodal antagonists in a suspended culture induces theappearance of markers of cell progenitors and pigment epithelium cells. Further treating thecells with retinoic acid and taurine activates the appearance of cells expressing photoreceptormarkers [75].

Several research groups have produced functional cardiomyocytes (CMs) in vitro from murine and human iPSCs [7781]. Cardiomyocytes producedfrom iPSC are very similar in characteristics (morphology, marker expression,electrophysiological features, and sensitivity to chemicals) to the CMs ofcardiac muscle and to CMs produced from differentiated ESCs. Moreover, murineiPSCs, when injected, can repair muscle and endothelial cardiac tissuesdamaged by cardiac infarction [77].

Hepatocytelike cell derivatives, dendritic cells, macrophages, insulinproducingcell clusters similar to the duodenal islets of Langerhans, and hematopoietic and endothelialcells are currently produced from murine and human iPSCs, in addition to thealreadylisted types of differentiated cells [8285].

In addition to directed differentiation in vitro , investigators apply mucheffort at producing patientspecific iPSCs. The availability ofpluripotent cells from individual patients makes it possible to study pathogenesis and carryout experiments on the therapy of inherited diseases, the development of which is associatedwith distinct cell types that are hard to obtain by biopsy: so the use ofiPSCs provides almost an unlimited resource for these investigations.Recently, the possibility of treating diseases using iPSCs was successfullydemonstrated, and the design of the experiment is presented in the figure. A mutant allele wassubstituted with a normal allele via homologous recombination in murine fibroblastsrepresenting a model of human sickle cell anemia. iPSCs were produced fromrepaired fibroblasts and then differentiated into hematopoietic cell precursors.The hematopoietic precursors were then injected into a mouse from which the skin fibroblastswere initially isolated (Fig. 1). As a result, the initialpathological phenotype was substantially corrected [86].A similar approach was applied to the fibroblasts and keratinocytes of a patient withFanconis anemia. The normal allele of the mutant gene producing anemia was introducedinto a somatic cell genome using a lentivirus, and then iPSCs were obtainedfrom these cells. iPSCs carrying the normal allele were differentiated intohematopoietic cells maintaining a normal phenotype [87].The use of lentiviruses is unambiguously impossible when producing cells to be introduced intothe human body due to their oncogenic potential. However, new relatively safe methods of genomemanipulation are currently being developed; for instance, the use of synthetic nucleasescontaining zinc finger domains allowing the effective correction of genetic defects invitro [88].

Design of an experiment on repairing the mutant phenotype in mice modeling sickle cell anemia development [2]. Fibroblasts isolatedfrom the tail of a mouse (1) carrying a mutant allele of the gene encoding the human hemoglobin -chain (hs) were used for iPSCproduction (2). The mutation was then repaired in iPSCs by means of homological recombination (3) followed by cell differentiationvia the embryoid body formation (4). The directed differentiation of the embryoid body cells led to hematopoietic precursor cells (5)that were subsequently introduced into a mouse exposed to ionizing radiation (6).

The induced pluripotent stem cells are an excellent model for pathogenetic studies at the celllevel and testing compounds possessing a possible therapeutic effect.

The induced pluripotent stem cells were produced from the fibroblasts of a patient with spinalmuscular atrophy (SMA) (SMAiPSCs). SMA is an autosomalrecessive disease caused by a mutation in the SMN1 ( survival motorneuron 1 ) gene, which is manifested as the selective nonviability of lower motor neurons. Patients with this disorder usually die at the age of about two years.Existing experimental models of this disorder based on the use of flatworms, drosophila, andmice are not satisfactory. The available fibroblast lines from patients withSMA cannot provide the necessary data on the pathogenesis of this disordereither. It was shown that motor neurons produced from SMAiPSCs canretain the features of SMA development, selective neuronal death, and the lackof SMN1 transcription. Moreover, the authors succeeded in elevating the SMNprotein level and aggregation (encoded by the SMN2 gene, whose expressioncan compensate for the shortage in the SMN1 protein) in response to the treatment of motorneurons and astrocytes produced from SMAiPSCs with valproate andtorbomycin [89;]. iPSCs and theirderivatives can serve as objects for pharmacological studies, as has been demonstrated oniPSCs from patients with familial dysautonomia (FDA) [90]. FDA is an inherited autosomal recessive disorder manifested as thedegeneration of sensor and autonomous neurons. This is due to a mutation causing thetissuespecific splicing of the IKBKAP gene, resulting in a decreasein the level of the fulllength IKAP protein. iPSCs were produced fromfibroblasts of patients with FDA. They possessed all features of pluripotent cells. Neuralderivatives produced from these cells had signs of FDA pathogenesis and low levels of thefulllength IKBKAP transcript. The authors studied the effect of threesubstances, kinetin, epigallocatechin gallate, and tocotrienol, on the parameters associatedwith FDA pathogenesis. Only kinetin has been shown to induce an increase in the level offulllength IKBKAP transcript. Prolonged treatment with kinetininduces an increase in the level of neuronal differentiation and expression of peripheralneuronal markers.

Currently, a broad spectrum of iPSCs is produced from patients with variousinherited pathologies and multifactorial disorders, such as Parkinsons disease, Downsyndrome, type 1 diabetes, Duchenne muscular dystrophy, talassemia, etc., whichare often lethal and can scarcely be treated with routine therapy [51, 87, 89, 9194]. The data on iPSCs produced by reprogramming somaticcells from patients with various pathologies are given in the Table 1.

Functional categories of M. tuberculosis genes with changed expression level during transition to the NC state

One can confidently state that both iPSCs themselves and their derivativesare potent instruments applicable in biomedicine, cell replacement therapy, pharmacology, andtoxicology. However, the safe application of iPSCbased technologies requires the use ofmethods of iPSCs production and their directed differentiation which minimizeboth the possibility of mutations in cell genomes under in vitro culturingand the probability of malignant transformation of the injected cells. The development ofmethods for human iPSC culturing without the use of animal cells (for instance, the feederlayer of murine fibroblasts) is necessary; they make a viralorigin pathogen transferfrom animals to humans impossible. There is a need for the maximum standardization ofconditions for cell culturing and differentiation.

This study was supported by the Russian Academy of Sciences Presidium ProgramMolecular and Cell Biology.

embryonic stem cells

induced pluripotent stem cells

neural stem cells

adipose stem cells

papillary dermal fibroblasts

cardiomyocytes

spinal muscular atrophy

iPCSs derived from fibroblasts of SMA patients

green fluorescent protein

long terminal repeat

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How Minaris is Tackling the Scalability Challenge in Cell and Gene Therapy: A Conversation with CEO, Dr. Hiroto Bando  geneonline

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Toward Personalized Cell Therapies by Using Stem Cells 2013: BioMed Research International  Wiley Online Library

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Cell therapy for heart disease and therapeutic cloning: will embryos re-enter the stem cell race?  Genethique

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It's official: The first use of induced pluripotent stem (iPS) cells in a human has proved safe, if not clearly effective. Japanese researchers reported in this week's issue of The New England Journal of Medicine (NEJM) that using the cells to replace eye tissue damaged by age-related macular degeneration (AMD) did not improve a patient's ...

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A scheme of the generation of induced pluripotent stem (IPS) cells. (1) Isolate and culture donor cells. (2) Transduce stem cell-associated genes into the cells by viral vectors. Red cells indicate the cells expressing the exogenous genes. (3) Harvest and culture the cells according to ES cell culture, using mitotically inactivated feeder cells (lightgray). (4) A small subset of the transfected cells become iPS cells and generate ES-like colonies.

iPSCs are typically derived by introducing products of specific sets of pluripotency-associated genes, or "reprogramming factors", into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and cMyc. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.[11] It is also clear that pro-mitotic factors such as C-MYC/L-MYC or repression of cell cycle checkpoints, such as p53, are conduits to creating a compliant cellular state for iPSC reprogramming.[12]

iPSC derivation is typically a slow and inefficient process, taking onetwo weeks for mouse cells and threefour weeks for human cells, with efficiencies around 0.010.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University, Japan, in 2006.[1] They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

In June 2007, three separate research groups, including that of Yamanaka's, a Harvard/University of California, Los Angeles collaboration, and a group at MIT, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells.

These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs.[13][14][15][16]

Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, Oct4, Sox2, Klf4, and cMyc, using a retroviral system,[17] while Thomson and colleagues used a different set of factors, Oct4, Sox2, Nanog, and Lin28, using a lentiviral system.[18]

Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible.[19][20] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck.[21][22] In 2010, iPSCs were derived from peripheral blood cells,[23][24] and in 2012, iPSCs were made from renal epithelial cells in the urine.[25]

Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[19][20] time it takes to expand the population of starting cells,[19] and the ability to differentiate into a given cell type.[26]

[citation needed]

The generation of induced pluripotent cells is crucially dependent on the transcription factors used for the induction.

Oct-3/4 and certain products of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table on the right summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small molecules that can mimic the effects of transcription factors. These compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanaka's traditional transcription factor method).[42] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[43] Deng et al. of Beijing University reported in July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[44][45]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the mesenchymal-epithelial transition (MET) process in which fibroblasts are pushed to a stem-cell like state, Ding's group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks.[46][47]

In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[48] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

Another key strategy for avoiding problems such as tumorgenesis and low throughput has been to use alternate forms of vectors: adenoviruses, plasmids, and naked DNA or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[43] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[49] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[35] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the PiggyBac Transposon System. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis.[citation needed]

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[50]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[51] On 4 June 2014, the lead author, Obokata agreed to retract both the papers[52] after she was found to have committed 'research misconduct' as concluded in an investigation by RIKEN on 1 April 2014.[53]

MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential.[54] Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed.[54] ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc.[55] MicroRNAs can also block expression of repressors of Yamanaka's four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.[54]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells.[58] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound.[67]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[68][69][70] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy subjects, providing insight into the pathophysiology of the disease.[71][72] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of diseases. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[73] Furthermore, combining hiPSC technology and small molecule or genetically encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening.[74][75][76][77][78]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human 'liver buds' (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocyte (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the 'liver' quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[79][80]

In 2021, a switchable Yamanaka factors-reprogramming-based approach for regeneration of damaged heart without tumor-formation was demonstrated in mice and was successful if the intervention was carried out immediately before or after a heart attack.[81]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[82][83]

Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.[84]

Beating cardiac muscle cells, iPSC-derived cardiomyocytes, can be mass-produced using chemically defined differentiation protocols.[85][86] These protocols typically modulate the same developmental signaling pathways required for heart development.[87] These iPSC-cardiomyocytes can recapitulate genetic arrhythmias and cardiac drug responses, since they exhibit the same genetic background as the patient from which they were derived.[88][89][90][91]

In June 2014, Takara Bio received technology transfer from iHeart Japan, a venture company from Kyoto University's iPS Cell Research Institute, to make it possible to exclusively use technologies and patents that induce differentiation of iPS cells into cardiomyocytes in Asia. The company announced the idea of selling cardiomyocytes to pharmaceutical companies and universities to help develop new drugs for heart disease.[92]

On March 9, 2018, the Specified Regenerative Medicine Committee of Osaka University officially approved the world's first clinical research plan to transplant a "myocardial sheet" made from iPS cells into the heart of patients with severe heart failure. Osaka University announced that it had filed an application with the Ministry of Health, Labor and Welfare on the same day.

On May 16, 2018, the clinical research plan was approved by the Ministry of Health, Labor and Welfare's expert group with a condition.[93][94]

In October 2019, a group at Okayama University developed a model of ischemic heart disease using cardiomyocytes differentiated from iPS cells.[95]

Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.[96]

The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 at the Riken Center for Developmental Biology in Kobe. However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015.[97] More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations).[98] iPSCs derived from skin cells from six patients with wet age-related macular degeneration were reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into the affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring were to last one to three years.[99][100]

In March 2017, a team led by Masayo Takahashi completed the first successful transplant of iPS-derived retinal cells from a donor into the eye of a person with advanced macular degeneration.[101] However it was reported that they are now having complications.[102] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and that it eliminates the need to use embryonic stem cells. However, these iPSCs were derived from another person.[100]

New clinical trials involving iPSCs are now ongoing not only in Japan, but also in the US and Europe.[103] Research in 2021 on the trial registry Clinicaltrials.gov identified 129 trial listings mentioning iPSCs, but most were non-interventional.[104]

To make iPSC-based regenerative medicine technologies available to more patients, it is necessary to create universal iPSCs that can be transplanted independently of haplotypes of HLA. The current strategy for the creation of universal iPSCs has two main goals: to remove HLA expression and to prevent NK cells attacks due to deletion of HLA. Deletion of the B2M and CIITA genes using the CRISPR/Cas9 system has been reported to suppress the expression of HLA class I and class II, respectively. To avoid NK cell attacks. transduction of ligands inhibiting NK-cells, such as HLA-E and CD47 has been used.[105] HLA-C is left unchanged, since the 12 common HLA-C alleles are enough to cover 95% of the world's population.[105]

A multipotent mesenchymal stem cell, when induced into pluripotence, holds great promise to slow or reverse aging phenotypes. Such anti-aging properties were demonstrated in early clinical trials in 2017.[106] In 2020, Stanford University researchers concluded after studying elderly mice that old human cells when subjected to the Yamanaka factors, might rejuvenate and become nearly indistinguishable from their younger counterparts.[107]

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Research is ongoing in Japan and overseas with the aim of realizing cell transplantation therapy using iPS cells. One safety issue of concern is the risk of tumor formation. CiRA in particular has focused its resources on this issue.

Broadly speaking, there are two main theories as to the mechanism whereby iPS cells may form tumors. One theory is that iPS cells form tumors in response either to reactivation of the reprogramming factors inserted into the cell or through damage caused to the original cell genome through the artificial insertion of the reprogramming factors. In response, a search was launched for optimal reprogramming factors which do not cause reactivation, and a method of generating iPS cells was developed in which reprogramming factors are not incorporated into the cell chromosomes and damage to the host genome is therefore avoided.

The other theory is that residues of undifferentiated cells - cells which have not successfully completed differentiation to the target cell type - or other factors lead to the formation of teratomas, a kind of benign tumor. This theory requires research on iPS cell proliferation and differentiation.

1. Search for optimal reprogramming factorsWhen Professor Shinya Yamanaka and his research team announced the successful generation of mouse iPS cells, one of the reprogramming factors they used was c-Myc, which is known to be an oncogene, that is a cancer-causing gene. There have been suggestions that this gene may be activated within the cell and cause a tumor to form. However, in 2010, CiRA Lecturer Masato Nakagawa and his team reported that L-Myc was a promising replacement factor for c-Myc. iPS cells created using L-Myc not only display almost no tumor formation, they also have a high rate of successful generation and a high degree of pluripotency.

2. Search for optimal vectorsWhen the reprogramming factors required to generate iPS cells were inserted into the cells of the skin or other body tissues, early methods employed a retrovirus or lentivirus as a "vector," or carrier. In these methods, the target genes are inserted into the viruses with the which the cells were then infected in order to deliver the target genes. When a retrovirus or lentivirus is used as a vector, however, the viruses are incorporated into the cells genomic DNA in a random fashion. This may cause some of the cells original genes to be lost, or in other cases activated, resulting in a risk of cancerous changes.

In 2008, to remedy this risk, CiRA Lecturer Keisuke Okita and his team explored the use of a circular DNA fragment known as a plasmid, which is not incorporated into the cell chromosome, as a substitute to the retrovirus or lentivirus methods. In this way, they developed a method of generating iPS cells in which the reprogramming factors are not incorporated into the cell chromosome. In 2011, Okita and his team further improved the efficiency generation by introducing into a self-replicating episomal plasmid six factors - OCT3/4, SOX2, KLF4, LIN28, L-MYC, and p53shRNA.

3. Establishing a method for generating and screening safe cellsOnce iPS cells have been induced to differentiate into the target somatic cells using the appropriate genes and gene insertion methods as explained above, the differentiated cells can be relied upon not to revert to the undifferentiated state. However, there may sometimes be a residue of undifferentiated cells which have not completed the process of differentiation into the target cells, and it is possible that these cells, however few, may form a tumor. Scientists had already established that different iPS cell lines, even if generated from the same individual using the same method, might nevertheless display differences in proliferation and differentiation potentials. This meant that, if iPS cells with low differentiation potential were used, there was a risk that a residue of cells in the cell group might fail to fully differentiate and result in the formation of a teratoma. In 2013, a team led by CiRA Lecturer Kazutoshi Takahashi and Dr. Michiyo Aoi, now an assistant professor at Kobe University, developed a simple method to screen for iPS cell lines that have high potential to differentiate into nerve cells. There is also a risk of tumorigenesis from genomic or other damage arising at the iPS cell generation stage or at the subsequent culture stage. CiRA Assistant Professor Akira Watanabe and his team have developed a sensitive method to detect genomic and other damage in iPS cells using the latest equipment.

4. Developing a reliable method of differentiation into the target cell typeIn cell transplantation therapy, iPS cells are not transplanted directly into the human body. Instead, cells are transplanted after first being differentiated into the target cell type. It is therefore important to develop a reliable method of inducing iPS cells to differentiate into the target cell type. CiRA is currently working to develop technology for differentiation into a range of different cell types from iPS cells. CiRA Professor Jun Takahashi and his team have developed a highly efficient method of inducing iPS cells to differentiate into dopamine-producing nerve cells. In 2014, CiRA Professor Koji Eto and his team reported a method of producing platelets from iPS cells that is both reliable and can yield high volumes. These findings represent a major step toward iPS cell-based regenerative medicine for nerve diseases such as Parkinsons disease and blood diseases such as aplastic anemia.

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Nobel Winner Shinya Yamanaka: Cell Therapy Is Very Promising For Cancer, Parkinsons, More  Forbes

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iPSCs Manufacturing for Cell-Based Therapies: A Market Analysis of Cell Types, Therapeutic Applications, Ma...  WhaTech

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Abu Dhabi Stem Cells Center partners with Japan-based Kyoto University and Rege Nephro  ZAWYA

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Eterna Therapeutics Enters Into Option and License Agreement with Lineage Cell Therapeutics to Develop Hypoimmune Pluripotent Cell Lines for Multiple Neurology Indications  Marketscreener.com

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While intrusion detection systems (IDS) monitor the network and send alerts to network administrators about potential threats, intrusion prevention systems take more substantial actions to control access to the network, monitor intrusion data, and prevent attacks from developing.

IPS evolved from IDS. IDS technology uses the same concept of identifying traffic and some of the similar techniques with the major difference being that IPS are deployed in-line and IDS are deployed off-line or on tap where they still inspect a copy of the entire traffic or flow but cannot take any preventive action. IDS are deployed to only monitor and provide analytics and visibility into the threats on the network.

Historically, IPS only reacted to cyber breaches, but this reactive stance is no longer satisfactory. IPS is now part of full network security suites, including threat monitoring, firewalls, intrusion detection, anti-virus, anti-malware, ransomware prevention, spam detection, and security analytics.

Recent trends in IPS include using AI to automate the detection process. The future of IPS technology extends network perimeter security with a multi-layered defense. Cloud IPS services perform this security function using extended detection, response, and endpoint protection.

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Advantages of IPS display panels:

If youve ever begun searching for a new computer screen, chances are youve probably come across the term IPS. Its at this point that you may be asking yourself,what is an IPS monitor?Andhow do I know if an IPS monitor is right for me?

To answer these questions we must first understand two things:

So, why is this important? A monitors panel technology is important because it affectswhat the monitor can doandfor which uses it is best suited.Each of the monitor panel types listed above offer their own distinctive benefits and drawbacks.

Choosing which type of monitor panel type to buy will depend largely on your intended usage and personal preference.After all, gamers, graphic designers, and office workers all have different requirements. Specific types of displays are best suited for different usage scenarios.

The specific type of LCD panel affects many different aspects of screen performance including:

Different panel technologies offer unique profiles with opinions on thebesttype of LCD being subjective and based on personal preference.

The reason for this is because none of the different monitor panel types as they are today can be classified as outstanding forallof the attributes mentioned above.

Below well take a look at how IPS, TN, and VA monitors affect screen performance and do some handy summaries of strengths, weaknesses, and best-case uses for each type of panel technology.

IPS monitors or In-Plane Switching monitors, leverage liquid crystals aligned in parallel to produce rich colors. IPS panels are defined by the shifting patterns of their liquid crystals. These monitors were designed to overcome the limitations of TN panels. The liquid crystals ability to shift horizontallycreates better viewing angles.

IPS monitors continue to be the display technology of choice for users that wantcolor accuracy and consistency. IPS monitors are really great when it comes tocolor performanceandsuper-wide viewing angles. The expansive viewing angles provided by IPS monitors help to deliver outstanding color when being viewed from different angles. One major differentiator between IPS monitors and TN monitors is that colors on an IPS monitor wont shift when being viewed at an angle as drastically as they do on a TN monitor.

IPS monitor variations include S-IPS, H-IPS, e-IPS and P-IPS, and PLS (Plane-to-Line Switching), the latter being the latest iteration. Since these variations are all quite similar, they are all collectively referred to as IPS-type panels. They all claim to deliver the major benefits associated with IPS monitors great color and ultra-wide viewing angles.

When it comes to color accuracy, IPS monitors surpass the performance of TN and VA monitors with ease. While latest-gen VA technologies offer comparative performance specs, pro users still claim thatIPS monitors reign supremein this regard.

Another important characteristic of IPS monitors is that they are able to support professional color space technologies, such asAdobe RGB. This is due to the fact that IPS monitors are able to offer more displayable colors, which help improve color accuracy.

In the past, response time and contrast were the initial weakness of IPS technology. Nowadays, however, IPS monitor response times have advanced to the point where they are even capable of satisfying gamers, thus resulting in a rising popularity inIPS monitors for gaming.

With regard to gaming, some criticisms IPS monitors include more visible motion blur coming as a result of slower response times, however the impact of motion blur will vary from user to user. In fact, mixed opinions about the drawbacks of IPS monitor for gaming can be found all across the web. Take this excerpt from one gaming technology writer for example: As for pixel response, opinions vary. I personally think IPS panels are quick enough for almost all gaming. If your gaming life is absolutely and exclusively about hair-trigger shooters, OK, youll want the fastest response, lowest latency LCD monitor. And that means TN. For the rest of us, and certainly for those who place even a modicum of importance on the visual spectacle of games, I reckon IPS is clearly the best panel technology. Read the full articlehere.

IPS monitors deliver ultra-wide 178-degree vertical and horizontal viewing angles. Graphic designers, CAD engineers, pro photographers, and video editors will benefit from using an IPS monitor. Many value the color benefits of IPS monitors and tech advances have improved IPS panel speed, contrast, and resolution. IPS monitors are more attractive than ever for general desktop work as well as many types of gaming. Theyre even versatile enough to be used in different monitor styles, so if youve ever compared an ultrawide vs. dual monitorsetup or considered the benefits ofcurved vs. flat monitors, chances are youve already come into contact with an IPS panel.

IPS Monitor Advantages:

IPS Monitor Drawbacks:

IPS Monitor Best Uses:

TN monitors, or Twisted Nematic monitors, are the oldest LCD panel types around. TN panels cost less than their IPS and VA counterparts and are a popular mainstream display technology for desktop and laptop displays.

Displays based on this monitor panel technology are ideal for cost-conscious consumers and entry-level multipurpose use.

Despite their lower perceived value, TN-based displays are the panel typepreferred by competitive gamers. The reason for this is because TN panels can achieve arapid response timeand thefastest refresh rates on the market(like this240Hz eSports monitor). To this effect, TN monitors are able toreduce blurring and screen tearingin fast-paced games when compared to an IPS or VA panel.

On the flip side,however, TN panel technology tends to be ill-suited for applications that benefit from wider viewing angles, higher contrast ratios, and better color accuracy. That being said, LED technology has helped shift the perspective and todays LED-backlit TN models offer higher brightness along with better blacks and higher contrast ratios.

The greatest constraint of TN panel technology, however, is a narrower viewing angle as TN monitors experience more color shifting than other types of panels when being viewed at an angle.

Todays maximum possible viewing angles are 178 degrees both horizontally and vertically (178/178), yet TN panels are limited to viewing angles of approximately 170 degrees horizontal and 160 degrees vertical (170 /160).

In fact, TN monitor can sometimes be easily identified by the color distortion and contrast shifting thats visible at the edges of the screen. As screen sizes increase, this issue becomes even more apparent as reduced color performance can even begin to be seen when viewing the screen from a dead-center position.

For general-purpose use, these shifts in color and contrast are often irrelevant and fade from conscious perception. However, this color variability makes TN monitors a poor choice for color-critical work like graphic design and photo editing. Graphic designers and other color-conscious users should also avoid TN displays due to their more limited range of color display compared to the other technologies.

TN monitors are the least expensive panel technology, making them ideal for cost-conscious businesses and consumers. In addition, TN monitors enjoy unmatched popularity with competitive gamers and other users who seek rapid graphics display.

TN Monitor Advantages:

TN Monitor Drawbacks:

TN Monitor Best Uses:

Vertical alignment (VA) panel technology was developed to improve upon the drawbacks of TN. Current VA-based monitors offer much higher contrast, better color reproduction, and wider viewing angles than TN panels. Variations you may see include P-MVA, S-MVA, and AMVA (Advanced MVA).

These high-end VA-type monitors rival IPS monitors as the best panel technology for professional-level color-critical applications. One of the standout features of VA technology is that it is particularly good at blocking light from the backlight when its not needed. This enables VA panels to display deeper blacks and static contrast ratios of up to several times higher than the other LCD technologies. The benefit of this is that VA monitors with high contrast ratios can deliver intense blacks and richer colors.

Contrast ratio is themeasured difference between the darkest blacks and the brightest whites a monitor can produce. This measurement provides information about the amount of grayscale detail a monitor will deliver. The higher the contrast ratio, the more visible detail.

These monitors also provide more visible details in shadows and highlights, making them ideal for enjoying videos and movies. Theyre also a good fit for games focused on rich imagery (RPG games for example) rather than rapid speed (such as FPS games).

MVA and other recent VA technologies offer the highest static contrast ratios of any panel technology. This allows for an outstanding visual experience for movie enthusiasts and other users seeking depth of detail. Higher-end, feature-rich MVA displays offer the consistent, authentic color representation needed by graphic designers and other pro users.

VA Monitor Advantages:

VA Monitor Drawbacks:

VA Monitor Best uses:

How does OLED compare to LCD?

There is another type of panel technology that differs from the monitor types discussed above and that is OLED or Organic Light Emitting Diode technology. OLEDs differ from LCDs because they use positively/negatively charged ions to light up every pixel individually, while LCDs use a backlight, which can create an unwanted glow. OLEDs avoid screen glow (and create darker blacks) by not using a backlight. One of the drawbacks of OLED technology is that it is usually pricier than any of the other types of technology explained.

Choosing the Right LCD Panel Technology

When it comes to choosing the right LCD panel technology, there is no single right answer. Each of the three primary technologies offers distinct strengths and weaknesses. Looking at different features and specs helps you identify which monitor best fits your needs.

With the lowest cost and fastest response times, TN monitors are great for general use and gaming. VA monitor offers a step up for general use. Maxed-out viewing angles and high contrast ratios make VA monitors great for watching movies and image-intensive gaming.

IPS monitors offer the greatest range of color-related features and remain the gold standard for photo editing and color-critical pro uses. Greater availability and lower prices make IPS monitors a great fit for anyone who values outstanding image quality.

LCD or Liquid Crystal Display is a type of monitor panel that embraces thin layers of liquid crystals sandwiched between two layers of filters and electrodes.

While CRT monitors used to fire electrons against glass surfaces, LCD monitors operate using backlights and liquid crystals. The LCD panel is a flat sheet of material that contains layers of filters, glass, electrodes, liquid crystals, and a backlight. Polarized light (meaning only half of it shines through) is directed towards a rectangular grid of liquid crystals and beamed through.

Liquid Crystals (LCs) are used because of their unique ability to maintain a parallel shape. Acting as both a solid and liquid, LCs are able to react quickly to changes in light patterns. The optical properties of LCs are activated by electric current, which is used to switch liquid crystals between phases. In turn, each pixel generates an RGB (red, green, blue) color based on the phase its in.

Note: When searching for monitors you can be sure to come across the term LED Panel at some point or another. An LED panel is an LCD screen with an LED (Light Emitting Diode) backlight. LEDs provide a brighter light source while using much less energy. They also have the ability to produce white color, in addition to traditional RGB color, and are the panel type used in HDR monitors.

Early LCD panels usedpassive-matrix technologyand were criticized for blurry imagery. The reason for this is because quick image changes require liquid crystals to change phase quickly and passive matrix technology was limited in terms of how quickly liquid crystals could change phase.

As a result,active-matrix technologywas invented andtransistors(TFTs) began being used to help liquid crystals retain their charge and change phase more quickly.

Thanks to active-matrix technology,LCD monitor panels were able to change images very quickly and the technology began being used by newer LCD panels.

Ultimately, budget and feature preferences will determine the best fit for each user. Among the available monitors of each panel type there will also be a range of price points and feature sets. Additionally, overall quality may vary among manufacturers due to factors related to a displays components, manufacturing, and design.

If youre interested in learning more about IPS monitors, you can take a look at some of theseprofessional monitorsto see if they would be the right fit for you.

Alternatively, if youre into gaming and are in the market for TN panel thesegaming monitoroptions may be along the lines of what youre looking for.

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IPS (in-plane switching) is a screen technology for liquid-crystal displays (LCDs). In IPS, a layer of liquid crystals is sandwiched between two glass surfaces. The liquid crystal molecules are aligned parallel to those surfaces in predetermined directions (in-plane). The molecules are reoriented by an applied electric field, whilst remaining essentially parallel to the surfaces to produce an image. It was designed to solve the strong viewing angle dependence and low-quality color reproduction of the twisted nematic field effect (TN) matrix LCDs prevalent in the late 1980s.[1]

The TN method was the only viable technology for active matrix TFT LCDs in the late 1980s and early 1990s. Early panels showed grayscale inversion from up to down,[2] and had a high response time (for this kind of transition, 1ms is visually better than 5ms). In the mid-1990s new technologies were developedtypically IPS and Vertical Alignment (VA)that could resolve these weaknesses and were applied to large computer monitor panels.

One approach patented in 1974 was to use inter-digitated electrodes on one glass substrate only to produce an electric field essentially parallel to the glass substrates.[3][4] However, the inventor was not yet able to implement such IPS-LCDs superior to TN displays.

After thorough analysis, details of advantageous molecular arrangements were filed in Germany by Guenter Baur et al. and patented in various countries including the US on 9 January 1990.[5][6] The Fraunhofer Society in Freiburg, where the inventors worked, assigned these patents to Merck KGaA, Darmstadt, Germany.

Shortly thereafter, Hitachi of Japan filed patents to improve this technology. A leader in this field was Katsumi Kondo, who worked at the Hitachi Research Center.[7] In 1992, engineers at Hitachi worked out various practical details of the IPS technology to interconnect the thin-film transistor array as a matrix and to avoid undesirable stray fields in between pixels.[8][9] Hitachi also improved the viewing angle dependence further by optimizing the shape of the electrodes (Super IPS). NEC and Hitachi became early manufacturers of active-matrix addressed LCDs based on the IPS technology. This is a milestone for implementing large-screen LCDs having acceptable visual performance for flat-panel computer monitors and television screens. In 1996, Samsung developed the optical patterning technique that enables multi-domain LCD. Multi-domain and in-plane switching subsequently remain the dominant LCD designs through 2006.[10]

Later, LG Display and other South Korean, Japanese, and Taiwanese LCD manufacturers adapted IPS technology.

IPS technology is widely used in panels for TVs, tablet computers, and smartphones. In particular, most IBM products was marketed as Flexview from 2004 to 2008 has an IPS LCDs with CCFL backlighting, and all Apple Inc. products marketed with the label Retina Display[11][12] feature IPS LCDs with LED backlighting since 2010.

In this case, both linear polarizing filters P and A have their axes of transmission in the same direction. To obtain the 90 degree twisted nematic structure of the LC layer between the two glass plates without an applied electric field (OFF state), the inner surfaces of the glass plates are treated to align the bordering LC molecules at a right angle. This molecular structure is practically the same as in TN LCDs. However, the arrangement of the electrodes e1 and e2 is different. Because they are in the same plane and on a single glass plate, they generate an electric field essentially parallel to this plate. The diagram is not to scale: the LC layer is only a few micrometers thick and so is very small compared with the distance between the electrodes.

The LC molecules have a positive dielectric anisotropy and align themselves with their long axis parallel to an applied electrical field. In the OFF state (shown on the left), entering light L1 becomes linearly polarized by polarizer P. The twisted nematic LC layer rotates the polarization axis of the passing light by 90 degrees, so that ideally no light passes through polarizer A. In the ON state, a sufficient voltage is applied between electrodes and a corresponding electrical field E is generated that realigns the LC molecules as shown on the right of the diagram. Here, light L2 can pass through polarizer A.

In practice, other schemes of implementation exist with a different structure of the LC molecules for example without any twist in the OFF state. As both electrodes are on the same substrate, they take more space than TN matrix electrodes. This also reduces contrast and brightness.[16]

Super-IPS was later introduced with better response times and colour reproduction.[17][unreliable source?]

Toward the end of 2010 Samsung Electronics introduced Super PLS (Plane-to-Line Switching) with the intent of providing an alternative to the popular IPS technology which is primarily manufactured by LG Display. It is an "IPS-type" panel technology, and is very similar in performance features, specs and characteristics to LG Display's offering. Samsung adopted PLS panels instead of AMOLED panels, because in the past AMOLED panels had difficulties in realizing full HD resolution on mobile devices. PLS technology was Samsung's wide-viewing angle LCD technology, similar to LG Display's IPS technology.[24]

Samsung asserted the following benefits of Super PLS (commonly referred to as just "PLS") over IPS:[25]

In 2012 AU Optronics began investment in their own IPS-type technology, dubbed AHVA. This should not be confused with their long standing AMVA technology (which is a VA-type technology). Performance and specs remained very similar to LG Display's IPS and Samsung's PLS offerings. The first 144Hz compatible IPS-type panels were produced in late 2014 (used first in early 2015) by AUO, beating Samsung and LG Display to providing high refresh rate IPS-type panels.[26][27]

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If you were to see the phrase Advanced Therapy Medicinal Product (ATMP) you might guess, an advanced treatment that is a medicine? but you will not get much more from this without doing a lot more homework.

Whoever decided that cell and gene therapy products should be described as Advanced Therapies was a little short sighted as to how this phrase would age and strangely so, once the phrase was coined and used by the FDA (note that the FDA has RMAT designation) it has been picked up and used all over the world. This is a bit of a disaster from a communications perspective for a society familiar with terms including stem cells, gene therapy, cell therapy, tissue engineering, all now being lumped to some extent under the banner Advanced Therapies. But, so it is and so we go forward. Now our focus is just to understand what Advanced Therapy Medicinal Products are and what they can offer!

ATMPs are next generation pharmaceuticals based on cells, gene therapy or tissue replacement. These pharmaceuticals offer novel technologies for new options for disease treatments. Where no treatment or no cure was available for a disease ATMPs may open new doors to enable:

You can find a more technology based classification at the end of this article.

You may have heard of some ATMPs CAR T (Yescarta, Kymriah), Luxturna gene therapy for blindness, Strimvelis gene therapy against bubble boy syndrome. These cell or recombinant (cut-paste) gene-based pharmaceuticals are revolutionizing treatments around the world and it is only early days. Patients who had no treatment options or patients who had exhausted all treatment options are finding new hope in ATMPs and many lives have been saved or transformed already. This field is moving incredibly fast; all of the major pharmaceutical companies have programs in ATMP. Interestingly, the COVID19 vaccines developed by AstraZeneca/Oxford, Pfizer/BioNTech, Moderna and Janssen are based on delivery of the same recombinant (cut-paste) gene technologies as some gene therapy ATMPs but the recombinant genes delivered for ATMPs introduce disease free human gene sequences to patients instead of coronavirus spike proteins.

The coronavirus pandemic is greatly accelerating capabilities of National healthcare agencies and clinics to be able to handle ATMP type technologies and treatment of basically the entire world population with such technologies is going to create unprecedented data on their safety. The Coronavirus pandemic is no doubt accelerating the ability to treat patients with untreatable or uncurable disease by at least 10 years.

Around the world promising initiatives to address the challenges of developing these complex gene and/or cell based pharmaceuticals have been popping up and rapidly developing in the last 10 years. Some well known examples include the British Cell and Gene Therapy Catapult, the Centre for Commercialization of Regenerative Medicine (CCRM) and the ATMP Sweden National Initiative. The breadth of need is extensive and unprecedented interactions required between pharmaceutical companies, hospitals, researchers and national authorities mean that technology is arguably right now not always the greatest challenge. There are many potential therapies trying to make their way to patients but the foundations for inclusion of these therapies in our society need to be worked out. How will we pay for an ungodly expensive therapy today that cures a patient in one treatment instead of treating this patient with a relatively cheap (or expensive) pill that they need to take every day for the rest of their life? In the end the curative therapy will be cheaper for society but the models on which our healthcare is based are not built with this type of opportunity in mind. A nice summary of the non-tech challenges in ATMP development can be seen in the program of the ATMP world tour April 26-30, 2021, where world leaders are coming together to discuss their approach to solutions. ATMP ATMP world tour 2021 (atmpsweden.se).

You may also find a video by the European Medicines Agency on ATMPs to be useful (below).

For those who want to go deeper into this topic of what ATMPs are from a technology or regulatory perspective this resource may also be useful ATMP What are ATMPs? (atmpsweden.se), including the Q&A to clarify what therapies are and are not regulated as ATMPs.

It is important to understand that ATMPs are pharmaceuticals or drugs, not all cell therapies are ATMPs. For example, a blood transfusion is a cell therapy but it is not a pharmaceutical so it is not an ATMP. Why is it not a pharmaceutical? The cells used for a blood transfusion have not been modified and will do the same job they did in the donor, thus this is just a transplant and the treating doctor is responsible for ensuring the safety and efficacy of the treatment is sufficiently risk free to benefit the patient. For more complex cell therapies , where manufacture is required or where cells are transplanted to a different organ, external and independent oversight is needed to ensure that these treatments have suitably low risk and sufficient benefit to the patient. These complex treatments are regarded as pharmaceuticals (i.e. drugs) and regulated by National/Regional public health agencies (FDA/EMA) who ensure the safety, efficacy, and security of these drug products. These treatments are now obliged to comply with Good Manufacturing Practice and undergo clinical trials towards market approval. This is EXPENSIVE and thus why many cowboys are trying to get around their treatments being classified as an ATMP as they do not want to spend their profits on proving it works or is safe if they can just buy a boat instead. Even if it did work, cowboys may treat a few thousand patients in their lifetime but a product that can be industrially produced and proven to be safe and efficacious could effectively treat millions.

We are imagining a healthcare future where we can modify a patients genome, replace diseased cells or tissues and/or selectively attack and remove defective cells. This is not a game. This is the reality of patients lives. Opportunities need to be brought forward ethically and safely. Today we can give a functional immune system to a baby born without one, and bring a terminally ill cancer patient into remission, but the potential in this industry to specifically target defective cells and genes, instead of pumping the whole body with drugs or radiation, means that in the next 10-20 years we will be looking at a very different approach to healthcare. Everyone is pepped for this, the patients, the doctors, the nurses, the caretakers. There are so many opportunities for new patient treatments that industry are working together to get this moving.

This is truly an exciting space to watch!

Advanced Therapy Medicinal Products (ATMP) pharmaceuticals based on:

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Cell and gene therapy products: what is an ATMP? - The Niche

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