By Sharon Rosenzweig-Lipson, CSO, Life Biosciences
Cell rejuvenation is rapidly becoming a hot topic in the development of new therapeutic modalities for various diseases.
The leading approach to cell rejuvenation currently under development uses 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.
During a person’s life, epigenetic marks (DNA methylation) occur in DNA that result in changes in gene expression patterns. These epigenetic changes accumulate over a person’s lifetime and can lead to large changes in gene expression with critical genes suppressed. Gene therapy is growing in popularity with approaches to treating a wide variety of diseases currently being developed. Unlike typical gene therapy approaches which directly alter genes, cell rejuvenation focuses on restoring cells to a more youthful state by removing epigenetic markers that suppress gene function.
Dr. Nobel Prize winning invention. Shinya Yamanaka that expression of four transcription factors can revert cells back to pluripotent stem cells by removing epigenetic tags is a fundamental advance in making this potential therapeutic approach possible. However, the limiting factor for therapeutic efficacy with the use of all four Yamanka factors is that cell identity is deleted and overexpression of one of these transcription factors (c-Myc) can lead to tumor formation.
Using partial epigenetic reprogramming to express only three transcription factor genes (Oct4, Sox2 and Klf4; collectively referred to as OSK) and eliminating the carcinogenic gene c-Myc, allows cells to be rejuvenated and returned to a more youthful state while retaining their original cellular identity and without form teratomas.
As the population ages, the prevalence of age-related eye diseases that lead to loss of visual acuity and eventually blindness continues to increase. While diseases such as wet age-related macular degeneration have seen a significant increase due to the use of VEGF inhibitors, other age-related eye diseases continue to lack effective long-term treatment.
Adeno-associated virus vector
Treatment for disorders related to retinal ganglion cell (RGC) function including advanced glaucoma or non-arteritic anterior ischemic optic neuropathy (NAION) is ineffective or non-existent. In recent years there has been increased interest in exploring the opportunities offered by gene therapy in hard-to-treat conditions including glaucoma and NAION. Various approaches are being evaluated to deliver these transcription factors to their targets. For example, an adeno-associated virus vector (AAV2) can be used to deliver OSK to RGC after intravitreal injection (IVT). Using such a system, OSK enhances RGC function across multiple models of aging, glaucoma, and NAION from mice to nonhuman primates. Alternative approaches using lipid nanoparticles to deliver mRNAs are advancing but may still require improvements in targeting specific cells/organs.
The value of cell rejuvenation by partial epigenetic reprogramming is only beginning to be explored with many diseases of aging poised to be tackled. With strong data 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 multiple organs throughout the body. With improvements in how we target each of these, the opportunities for the treatment of aging diseases using cell-rejuvenation approaches, not only for age-related eye diseases but also for other tissues are certainly very promising.