AAV Gene Therapy for MPS1-associated Corneal Blindness

Area of Science:

• Ophthalmology
• Genetics
• Gene Therapy

Background:

• Mucopolysaccharidosis type 1 (MPS1) patients often develop severe cornea clouding and blindness despite cord blood transplantation.
• Current treatments like corneal transplants have high rejection rates in MPS1 children, leaving no effective vision-saving options.

Purpose of the Study:

• To investigate a gene addition strategy using adeno-associated virus (AAV) vectors to prevent and potentially reverse blindness in MPS1 patients.
• To evaluate the safety and efficacy of delivering the alpha-L-iduronidase (IDUA) gene to human corneas.

Main Methods:

• Validated a codon-optimized IDUA cDNA expression cassette (opt-IDUA) for IDUA production in MPS1 patient fibroblasts.
• Identified an AAV8 and 9 chimeric capsid (8G9) as the most efficient for corneal transduction.
• Administered AAV8G9-opt-IDUA via intrastromal injection into human corneas and assessed IDUA activity and cell viability.

Main Results:

• Demonstrated widespread transduction of human corneas, including endogenous IDUA-producing cells.
• Achieved a >10-fold supraphysiological increase in IDUA activity post-injection.
• Observed no significant apoptosis related to AAV vectors or IDUA in human corneas or patient fibroblasts.

Conclusions:

• Preclinical data indicate safe and efficient delivery of the IDUA gene to human corneas.
• This gene therapy approach holds potential for preventing and reversing MPS1-associated corneal blindness.