The National MPS Society’s Research Program funds basic, translational, and clinical research. In 2017 we awarded grant funding to “MPS I Cornea Clouding AAV Gene Therapy Project,” with Dr. Matthew Hirsch, University of North Carolina. The aims of the science are to address corneal blindness and reversal of corneal clouding. The “simple” AAV8-opt-IDUA (adeno-associated virus containing codon-optimized α-L-iduronidase) gene addition strategy is delivered through an intrastromal injection. Results from this study are outlined in a new article in Molecular Therapy titled “Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits.”
Original experiments occurred in collaboration with Dr. Brian Gilger at North Carolina State University evaluating efficacy of AAV-IDUA in canine models. Experiments quickly noted that the MPS I canine colonies resulted in significant improvements of the cornea within nine weeks. Continued study demonstrated improvement in corneal clouding in 100% of the animal subjects within the colony with minimal side effects and little to no systemic involvement beyond the eye.
Corneal clouding is a predominate symptom of MPS I and many patients receive corneal transplants as the long-term management as the disease progresses and patients begin experiencing resulting blindness. Science in AAV-IDUA vectors opens the door for patients to consider a less invasive procedure in the future. Corneal clouding is not limited to MPS I; research in corneal gene therapy for MPS I may be translatable to other syndrome types, including MPS IV, VI, and VII.
The current study demonstrated AAV-opt-IDUA present in injected corneas with effectiveness across a variety of dosages. Safety and efficacy were demonstrated in both dogs and rabbits and concluded that this research indicates a potential to provide treatment to both prevent and reverse blindness for individuals with MPS I. Peripheral tissue exposure (outside of the eye) was limited and both the lowest effective dose of AAV8-opt-IDUA (at 1e9 vg, the lowest dose of AAV gene therapy administered to humans in any context) and dosages 10-fold higher (1e10 vg) demonstrated tolerability and all rabbits having clearing within 24 hours. Within 4-7 days following injection, the eyes were considered “clinically normal.”
The lifelong impact of an MPS I patient managing blindness due to corneal clouding is unnecessary, and science is evolving beyond transplants into gene therapy options. The National MPS Society is proud of this collaboration, and grateful for the scientists targeting this groundbreaking research. Our program continues to seek innovative science reflecting the unmet need of our patient population.
Song, L., Bower, J. J., Llanga, T., Salmon, J. H., Hirsch, M. L., & Gilger, B. C. (2020). Ocular Tolerability and Immune Response to Corneal Intrastromal AAV-IDUA Gene Therapy in New Zealand White Rabbits. Molecular Therapy – Methods & Clinical Development, 18, 24–32. doi: 10.1016/j.omtm.2020.05.014