OSK Reprogramming (Myc-free) — Gene Therapy & Genetic Interventions
Safer partial reprogramming using only Oct4, Sox2, and Klf4 without the oncogenic c-Myc factor.
Overview
OSK reprogramming uses three of the four Yamanaka factors (Oct4, Sox2, Klf4) without c-Myc, which is a known oncogene. David Sinclair's lab at Harvard demonstrated that AAV-delivered OSK restored vision in aged mice by regenerating retinal ganglion cells and reversing epigenetic age of the optic nerve. This landmark study (Lu et al., 2020, Nature) showed that OSK expression reversed DNA methylation age, restored youthful gene expression, and promoted axon regeneration after optic nerve crush injury. Life Biosciences and other companies are pursuing OSK-based therapies.
Indications
- Glaucoma and optic nerve degeneration (lead preclinical indication)
- Age-related vision loss
- Peripheral nerve injury repair
- Epigenetic age reversal in neural tissue
- Broader tissue rejuvenation (exploratory)
Mechanism of Action
AAV-delivered Oct4, Sox2, and Klf4 are expressed in target cells under inducible promoter control
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| AAV2-OSK (intravitreal) | 1 x 10^10 - 10^12 vg per eye | Single injection | Doxycycline-inducible system; ocular delivery |
| AAV-OSK (systemic) | Study-specific | Single infusion | Systemic delivery under preclinical investigation |
Safety & Contraindications
- Omission of c-Myc significantly reduces but does not eliminate oncogenic risk
- Oct4 has been implicated in some cancers; monitoring essential
- AAV delivery to the eye (intravitreal) is well-established and relatively safe
- Systemic delivery of OSK carries higher risk than local ocular delivery
- Long-term effects of in vivo reprogramming on tissue homeostasis unknown
- No human clinical trials initiated for age reversal indication