Nonhuman primates (NHPs) are highly translational models in drug development and are widely used in preclinical efficacy and safety studies1. Due to genotype similarities with humans, in vitro NHP stem cell lines have started gaining traction within the drug discovery community as translational models to evaluate preclinical efficacy and safety. Initially, pluripotent stem cells were initially developed from mice followed by humans. Human embryonic stem cells (ESCs) were first described in 19982 but faced significant challenges due to ethical issues and societal pressures. A major breakthrough was reported in 2006 when Yamanaka and colleagues described the development of human induced pluripotent stem cells (iPSCs) that were reprogrammed using specific transcription factors3. Since the first report, human iPSC lines have been widely developed and used for basic research, in vitro assays for drug development and are the foundation of cell therapies and regenerative medicines. Methods and protocols to develop novel human stem cell lines are widely available but, interestingly, the development and use of NHP stem cell lines have somewhat lagged behind. One reason could be that reprogramming NHP cells to iPSCs has lower efficiency and the protocols are more complex compared to human cell reprogramming1. For example, NHP iPSC reprogramming require feeder cells and xenogeneic serum and depending on the NHP species, can take several weeks1. Despite technical challenges, NHP stem cell lines have been successfully developed and are being used in multiple applications including regenerative drug development and cell therapies as well as primate developmental biology studies.
One of the key applications of NHP pluripotent stem cells is preclinical testing of cell therapies. During preclinical development, the dosage, route of administration, implantation efficiency, short- and long-term efficacy and host rejection need to be evaluated. NHP iPSCs are well suited to test cell therapies in NHP models prior to clinical trials4. NHP models are well suited for longitudinal studies to evaluate host rejection and graft vs host disease as they have an extended life span and large bodies that is amenable to imaging, surgical and sampling methods that are used in the clinic4. NHP pluripotent stem cells have been reported to be similar to human stem cells so the preclinical data on cell therapies is translatable to human patients. A key application of NHP pluripotent stem cells is the evaluation of immunogenicity responses to cell therapies. The easiest approach to avoid immune reactions is to focus on autologous cell therapies, which have limited scalability and require complex supply chain logistics among other challenges. Allogeneic cell therapies are scalable and easier to manufacture but typically induce host rejection both locally and systemically. Therefore, in order to safely develop allogeneic cell therapies, it is necessary to analyze immune risk and tissue damage caused by the host immune system. The NHP immune system is very similar to human so testing NHP pluripotent stem cell derived therapies in an NHP model is a good model to evaluate immunogenicity4.
NHP pluripotent stem cells have applications in regenerative medicine. For example, researchers in Göttingen Germany reported a new method to reprogram NHP skin fibroblasts to iPS cells that were successfully differentiated into cardiac muscle cells1. The NHP iPSC derived cardiomyocytes had self-organizing capacity and were shown to generate beats via microelectrode array (MEA) analysis1. Another growing area of interest is regenerative therapies for neurodegenerative diseases such as Parkinson’s disease (loss of dopaminergic neurons) and Huntington’s disease (loss of basal ganglia neurons). Over the past decade, a few groups have developed autologous transplantation NHP models for Parkinson’s disease4 and have continued to improve the transplantation process. A recent publication demonstrated the most advanced model where dopamine neural progenitor cells were transplanted in NHP models of Parkinson’s disease and were shown to reduce disease symptoms significantly with lower immune risk over a 2-year period5. As expected, autologous transplantation showed longer engraftment with low immune risk compared to allogeneic transplantation.
In summary, it is clear that NHP pluripotent stem cells have disease specific applications to evaluate advanced modalities such as cell therapies. It is likely that the next generation of NHP iPSCs will have improved reprogramming and differentiation efficiencies and NHP stem cells will have an important role in the translational drug development toolkit.
References:
1https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349583/
2https://pubmed.ncbi.nlm.nih.gov/9804556/
3https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951134/
Leave a Reply