Partial Cellular Reprogramming for Epigenetic Age 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), result in toxicities like teratoma formation and dysplasia, and fail to maintain cellular identity, limiting their application in vivo.
Innovation Solution
The use of spatially and temporally controlled expression of OCT4 and SOX2, along with KLF4, without c-Myc, to rejuvenate cells by reversing epigenetic marks associated with aging, thereby maintaining cellular identity and preventing complete reprogramming.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Yamanaka factors (OCT4, SOX2, c-Myc, and KLF4) are used for cellular reprogramming, then cellular rejuvenation and epigenetic mark reversal are achieved, but toxicity and teratoma formation 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 eliminates the toxic and teratoma-forming effects of c-Myc while preserving the rejuvenation capabilities of the remaining factors.
Solution Approach 2:
The patent applies partial reprogramming by using a subset of the full Yamanaka factors (omitting c-Myc) and controlling the expression timing and intensity. This partial action achieves sufficient epigenetic reversal without the excessive action that would cause toxicity and teratoma formation.
2Reliability
If complete reprogramming is achieved using Yamanaka factors, then epigenetic marks are reversed, but cellular identity is lost
Solution Approach 1:
The patent applies partial reprogramming rather than complete reprogramming by using only three factors (OCT4, SOX2, KLF4) instead of all four Yamanaka factors, and by controlling expression levels and timing. This partial action reverses epigenetic marks associated with aging while preserving enough cellular identity for functional maintenance.
Solution Approach 2:
The patent employs dynamic control of transcription factor expression through inducible systems and temporal regulation. Expression is activated only when needed for epigenetic reversal and then downregulated or turned off to prevent complete loss of cellular identity, creating a dynamic balance between rejuvenation and identity preservation.
Data Source
AI summary
Provided herein are engineered nucleic acids (e.g., expression vectors, including viral vectors, such as lentiviral vectors, adenoviral vectors, AAV 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).