In vivo adenine base editing ameliorates Rho-associated autosomal dominant retinitis pigmentosa

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Mutations in the Rhodopsin (RHO) gene are the primary cause of autosomal dominant retinitis pigmentosa (adRP), with most being pathogenic gain-of-function point mutations.
• Current treatments for adRP focus on allele silencing or ablation, as RHO protein replacement offers limited therapeutic benefit.

Purpose of the Study:

• To investigate the efficacy of an adenine base editor (ABE)-mediated therapeutic strategy for adRP caused by RHO point mutations in vivo.
• To screen and verify correctable pathogenic RHO mutations, including T17M, Q344ter, and P347L.

Main Methods:

• Development of two adRP animal models harboring class 1 (Q344ter) and class 2 (T17M) mutations.
• In vivo delivery of a dual adeno-associated virus (AAV)-packaged adenine base editor (ABE) system to correct the targeted RHO mutations.
• Assessment of the therapeutic effects, including mutation correction, photoreceptor survival, retinal function, and visual behavior restoration.

Main Results:

• The dual AAV-delivered ABE system effectively repaired both Q344ter and T17M mutations in vivo.
• Early intervention using ABE8e demonstrated efficient correction of the Q344ter mutation, significantly delaying photoreceptor death.
• Restoration of retinal function and visual behavior was observed in the treated animal models.

Conclusions:

• Adenine base editor (ABE) mediated gene editing presents a promising therapeutic alternative for treating Rhodopsin (RHO) mutation-associated autosomal dominant retinitis pigmentosa (adRP).
• This study provides a viable spacer-mediated point mutation correction therapy for dominantly inherited ocular disorders.