Partial Cellular Reprogramming with OCT4 and SOX2 for Aging Reversal
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Solution Overview
Problem
Existing methods for cellular reprogramming, such as using the Yamanaka factors (OCT4, SOX2, c-Myc, and KLF4), induce complete pluripotency leading to teratomas and acute toxicity, and fail to maintain cellular identity for tissue and organ integrity.
Innovation Solution
Spatially and temporally controlled expression of OCT4 and SOX2, with or without KLF4, in the absence of c-Myc, to rejuvenate cells by reversing epigenetic marks associated with aging without complete reprogramming, using inducible promoters and AAV delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If complete reprogramming with Yamanaka factors (OCT4, SOX2, c-Myc, and KLF4) is used to reverse cellular aging, then cellular youthfulness and regeneration capacity are improved, but teratoma formation and acute toxicity occur
Solution Approach 1:
The patent extracts and removes c-Myc from the Yamanaka factor combination, using only OCT4, SOX2, and KLF4 for reprogramming. This extraction of the harmful component (c-Myc) eliminates teratoma formation and acute toxicity while preserving the beneficial reprogramming effects on cellular aging and regeneration
Solution Approach 2:
The patent applies partial reprogramming action by using a subset of the original Yamanaka factors (3 out of 4) and controlling the duration of treatment. This partial action is sufficient to reverse epigenetic aging marks without triggering the harmful effects of complete reprogramming, achieving the desired effect with less intensity
2Reliability
If complete reprogramming is performed to restore cellular youthfulness, then epigenetic marks associated with aging are reversed, but cellular identity is lost compromising tissue and organ integrity
Solution Approach 1:
The patent uses partial reprogramming with OCT4, SOX2, and KLF4 for a controlled duration to achieve partial epigenetic rejuvenation. This partial action is sufficient to reverse aging marks (as measured by epigenetic clocks) while stopping before complete reprogramming occurs, thereby preserving cellular identity and tissue integrity
Solution Approach 2:
The patent employs feedback control by monitoring epigenetic aging markers and treatment response to determine when to stop reprogramming. This feedback mechanism ensures treatment is discontinued at the optimal point where aging marks are reversed but cellular identity is maintained, preventing over-reprogramming
Data Source
AI summary
Provided herein are engineered nucleic acids (e.g., expression vectors, including viral vectors, such as lentiviral vectors, adenoviral vectors, AV vectors, herpes viral vectors, and retroviral vectors) that encode OCT4; KLF4; SOX2; or any combination thereof that are useful, for example, in inducing cellular reprogramming, tissue repair, tissue regeneration, organ regeneration, reversing aging, or any combination thereof. Also provided herein are recombinant viruses (e.g., lentiviruses, alphaviruses, vaccinia viruses, adenoviruses, herpes viruses, retroviruses, or AAVs) comprising the engineered nucleic acids (e.g., engineered nucleic acids), engineered cells, compositions comprising the engineered nucleic acids, the recombinant viruses, engineered cells, engineered proteins, chemical agents that are capable of activating expression of OCT4; KLF4; SOX2; or any combination thereof, an engineered protein selected from the group consisting of OCT4; KLF4; SOX2; or any combination thereof, an antibody capable of activating expression of OCT4; KLF4; SOX2; or any combination thereof, and methods of treating a (e.g., ocular disease), preventing a disease (e.g., ocular disease), regulating (e.g., inducing or inducing and then stopping) cellular reprogramming, regulating tissue repair, regulating tissue regeneration, or any combination thereof).