There are several examples of dramatic genomic changes that appear when cells
are reprogrammed. Studies of some trinucleotide repeat diseases have reported
changes in the repeat length following reprogramming. Specifically, in
Friedreich ataxia, the GAA/TTC triplet repeat length in the FXN (frataxin) gene
appeared to change following reprogramming of patient fibroblasts
Although the probability of an FDA-approved hPSC-derived cell
therapy causing harm to a patient appears to be low, the consequences of adverse
events are enormous. There is an important lesson from the failures in early
gene therapy trials. If even one patient is harmed in an FDA-approved trial
using hPSC derivatives, all further trials will be in serious jeopardy, and the
promise of stem cell therapy will be put on indefinite hold.
Human pluripotent stem cells (hPSCs) are known to acquire genomic changes as they proliferate and differentiate. Despite concerns that these changes will compromise the safety of hPSC-derived cell therapy, there is currently scant evidence linking the known hPSC genomic abnormalities with malignancy. For the successful use of hPSCs for clinical applications, we will need to learn to distinguish between innocuous genomic aberrations and those that may cause tumors. To minimize any effects of acquired mutations on cell therapy, we strongly recommend that cells destined for transplant be monitored throughout their preparation using a high-resolution method such as SNP genotyping.
In the 15 years since the derivation of human pluripotent stem cells (hPSCs)2 was first reported, the research community has been moving steadily toward the goal of using these remarkable cells as replacements for tissues that are lost as a result of heart disease, diabetes, neurodegenerative disease, and skeletal and muscular disorders and injuries. The progress toward therapies has required incremental improvements in culture and differentiation methods, GMP and industrial-scale cell culture, legal permissions, and considerable investment from both public and private entities. At the same time that new hPSC therapies are being launched, concerns regarding their safety remain a major hurdle. In the worst case scenario, the transplanted cells may harm the patient by becoming cancerous or inducing cancers. For cell types derived from hPSCs, there are two major concerns about tumorigenicity. The first is intrinsic to pluripotency; undifferentiated hPSCs generate teratomas, germ cell tumors that are usually benign, when they are transplanted to immunodeficient mice. Although all of the clinical applications require the cells to be differentiated, there is concern about residual undifferentiated cells in transplanted populations. Second, mutations in transplanted cells are a major concern because genomic mutations are associated with tumorigenicity. In this minireview, we summarize the available information about instability in the genomes of hPSCs and consider the potential impact of genomic instability on the safety of current and future hPSC-derived transplantation therapies.
via Juan Carlos Baiges Friedreich
Ataxia Scientific News