Church Lab Combinatorial Aging Gene Therapy — Gene Therapy & Genetic Interventions
George Church's multiplex longevity gene therapy approach targeting multiple aging pathways with a single treatment.
Overview
George Church's lab at Harvard has pioneered combinatorial gene therapy approaches for aging, systematically testing combinations of longevity-associated genes delivered via AAV vectors. In a landmark 2019 preprint, they demonstrated that a combination of three genes (FGF21, sTGFBR2, and aKlotho) delivered via AAV could simultaneously reverse obesity, type 2 diabetes, heart failure, and kidney failure in aged mice. The combinatorial approach is based on the hypothesis that aging is a multi-factorial process requiring multi-target intervention. This work led to the founding of Rejuvenate Bio.
Indications
- Multi-organ aging reversal
- Age-related metabolic syndrome
- Heart failure in aging
- Kidney function decline
- Obesity and insulin resistance
Mechanism of Action
Three AAV8 vectors transduce hepatocytes, which become biofactories secreting FGF21, sTGFBR2, and soluble Klotho into circulation
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| AAV triple combination (FGF21 + sTGFBR2 + aKlotho) | 3 x 10^11 vg per vector | Single injection | Murine dose; human-equivalent dose not established |
Evidence Grade
GRADE C
Safety & Contraindications
- Multi-gene delivery complexity increases unpredictable interactions
- AAV dose requirements scale with number of transgenes
- Individual gene overexpression may have tissue-specific adverse effects
- FGF21 overexpression can cause bone loss in preclinical models
- TGF-beta pathway manipulation affects wound healing and immune function
- Human translation requires extensive safety characterization