Gene therapy for ocular hypertension using hfCas13d-mediated mRNA targeting

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Glaucoma causes irreversible vision loss due to elevated intraocular pressure (IOP) and retinal ganglion cell (RGC) damage.
• Current glaucoma treatments targeting aqueous humor dynamics are often insufficient for effective disease management.

Purpose of the Study:

• To develop and evaluate a targeted gene therapy for glaucoma using RNA editing to reduce aqueous humor production.
• To assess the efficacy of knocking down aquaporin 1 (AQP1) and carbonic anhydrase 2 (CA2) genes in lowering IOP and preserving RGCs.

Main Methods:

• Utilized Cas13 RNA editing systems to target and knock down AQP1 and CA2 genes, which are involved in aqueous humor production.
• Tested the hfCas13d-mediated knockdown in wild-type mice and a corticosteroid-induced glaucoma mouse model.
• Evaluated IOP levels, aqueous production, outflow facility, and RGC survival.

Main Results:

• hfCas13d-mediated knockdown of AQP1 and CA2 significantly reduced IOP in both wild-type and glaucoma mouse models.
• The IOP reduction was attributed to decreased aqueous humor production, with no impact on outflow facility.
• The treatment significantly promoted RGC survival compared to untreated controls.

Conclusions:

• CRISPR-Cas-based gene editing targeting AQP1 and CA2 offers a promising therapeutic strategy for lowering IOP.
• This approach demonstrates potential for treating glaucomatous optic neuropathy by reducing IOP and preserving vision.