Development of a Gene Therapy Approach for the Treatment of Neurofibromatosis Type 2
Abstract
Neurofibromatosis type 2 (NF2) is a tumor predisposing disease caused by loss of the NF2 gene and is associated with multiple nervous system tumors, including vestibular schwannomas (VS) that arise from Schwann cells. These nervous system tumors lead to tinnitus, deafness, disequilibrium, and facial paralysis, along with presenile cataracts and peripheral nerve tumors. Brainstem compression leading to hydrocephalus, stroke and death are rare, but deafness and facial paralysis are common. Although NF2 is a rare disease (1:33,000), sporadic VS and meningiomas are also caused by pathogenic NF2 variants in 95% of sporadic VS and in 50% of sporadic meningiomas. Meningiomas are the most common intracranial tumors, with an incidence in the U.S. of 8.33 per 100,000 person-years. Sporadic VS are the sixth most common intracranial tumor at 1.09 per 100,000 patient years. Overall, the prevalence of these tumors resulted in 31,990 meningiomas and 4,100 VS in the U.S. in 2019. The quality of life of NF2 patients is similar to that of patients with cancer. Additionally, NF2 patients have higher levels of psychosocial stressors, disease-related anxiety, personal and financial stress, and lack of social support. Current treatment strategies for NF2 involve surgery and stereotactic radiation (SR), both of which are associated with worsening functional performance. Furthermore, surgery and SR are aimed primarily at slowing disease progression, rather than halting or reversing the disease process. No FDA-approved chemotherapeutic agents exist for the treatment of NF2, although multiple agents are in clinical trials. Disease-associated changes of the NF2 gene are stable mutations that are suitable for correction with targeted gene therapy. Adeno-associated virus (AAV) viral vectors have helped usher in the age of gene therapy and are clinically approved for several indications, including a form of blindness and spinal muscular atrophy. Successful gene therapy would be liberating for NF2 patients, with prevention of schwannoma formation and preservation of critical hearing, balance, and cranial nerve function. In this proposal, we plan to develop a novel AAV-based gene therapy to add the NF2 gene back to Schwann cells that have lost the NF2 gene and thereby treat the schwannomas and hearing loss that NF2 patients currently experience. We will test the idea that NF2 gene replacement, using our novel capsid-promoter combinations, will (1) cause regression of human schwannomas and (2) preserve hearing in mice lacking Nf2 in Schwann cells, in the context of an otherwise normal auditory and nervous system. Successful gene therapy would be liberating for NF2 patients, with prevention of schwannoma formation and preservation of critical hearing, balance, and cranial nerve function.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310284
Entities
People
- David Jung
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army