By Sharon Rosenzweig-Lipson, CSO, Life Biosciences
Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases.
The leading approaches to cellular rejuvenation currently in development utilize epigenetic reprogramming to achieve this goal. Epigenetics is the study of how positive and negative lifestyle factors (exercise, smoking, drinking, etc.), aging, disease and injury all influence how effectively our genes work.
Over the course of one’s life, epigenetic marks (DNA methylation) occur on DNA resulting in changes in the pattern of gene expression. These epigenetic changes accumulate during one’s lifespan and can lead to vast changes in gene expression with critical genes being repressed. Gene therapy has been gaining in popularity with approaches to treat a wide range of diseases currently under development. Unlike typical gene therapy approaches that directly alter genes, cellular rejuvenation focuses on restoring cells to a more youthful state by removing the epigenetic marks that are repressing gene function.
Cellular rejuvenation: the ‘Yamanaka factors’
Dr. Shinya Yamanaka’s Nobel Prize winning discovery that the expression of four transcription factors could return a cell back to a pluripotent stem cell by removing epigenetic marks was a foundational advancement in making this potential therapeutic approach possible. The limiting factor for therapeutic efficacy with the use of all four Yamanka factors, however, is that cell identity is erased and over-expression of one of these transcription factors (c-Myc) can cause tumor formation.
Using partial epigenetic reprogramming to only express three transcription factor genes (Oct4, Sox2 and Klf4; collectively called OSK) and removing the carcinogenic gene c-Myc, allows cells to be rejuvenated and returned to a more youthful state while maintaining their original cellular identity and without forming teratomas.
As the population ages, the prevalence of age-related eye diseases leading to visual acuity loss and ultimately blindness continues to increase. While diseases such as wet age-related macular degeneration have seen significant improvements due to the use of VEGF inhibitors, other age-related eye diseases continue to lack effective long-term treatments.
Adeno-associated viral vectors
Treatments for disorders related to retinal ganglion cell (RGC) function including advanced glaucoma or non-arteritic anterior ischemic optic neuropathy (NAION) are either lacking in meaningful efficacy or non-existent. In recent years there has been an increased interest in exploring the opportunities offered by gene therapies in difficult to treat conditions including glaucoma and NAION. Multiple approaches are being evaluated to deliver these transcription factors to their targets. For example, an adeno-associated viral vector (AAV2) can be used to deliver OSK to RGCs following intravitreal (IVT) injection. Using such a system, OSK improves RGC function across a wide range of models of aging, glaucoma and NAION from mouse to nonhuman primate. Alternate approaches using lipid nanoparticles to deliver mRNA are advancing but may still require improvement in specific cell/organ targeting.
The value of cellular rejuvenation by partial epigenetic reprogramming is just beginning to be explored with numerous diseases of aging ready to be addressed. With strong data already supporting ophthalmological indications, diseases such as glaucoma and NAION will likely be the earliest areas for therapeutic intervention. Patterns of epigenetic changes have been shown to impact numerous organs throughout the body. With improvements in how we target each one, the opportunities for treatment of diseases of aging utilizing a cellular rejuvenation approach, not only for age-related eye diseases but also for other tissues certainly holds great promise.