Development of a Novel AAV9 Gene Replacement Therapy for Neurofibromatosis Type 2

PROJECT SUMMARY/ABSTRACT The severe genetic disorder Neurofibromatosis type 2 (NF2) causes tumor growth throughout the nervous system due to lack of expression of the tumor suppressor protein Merlin. These tumors cause progressive, debilitating neurological symptoms, including pain, nerve dysfunction, deafness, paralysis, vision problems, and balance disruption, leading to a substantially shortened lifespan of approximately 36 years. The socio-economic burden of this disease and the physical and psychological toll on patients and families remain devastating since current treatment options (surgery, chemotherapy, and radiation) do not work on the majority of patients and have severe side effects. There are currently no FDA-approved treatment options available for NF2 patients. To address this unmet need, Merlin Therapeutics is developing an adeno-associated viral vector 9 (AAV9) gene therapy expressing a healthy copy of the NF2 coding sequencing under the control of a truncated but functional NF2 promoter sequence. This gene therapy approach is unique because it is designed to allow the expression of the Merlin protein in all cell types affected by the disease at adequate levels. Extensive preliminary studies compared multiple promoter constructs and showed that the therapeutic lead vector is efficacious in delivering the Merlin protein and rescuing tumor characteristics in vitro in patient Schwann cell lines carrying multiple different NF2 mutations and in primary human vestibular schwannoma cells isolated from a patient tumor sample. Moreover, intratumoral injections of the treatment successfully reduced tumor growth in a schwannoma xenograft mouse model in vivo. The objective of the current project is to validate the existing preliminary data and gather additional information on dose-response and safety, as well as confirm promoter activity and biodistribution of the lead gene therapy candidate in a in larger animal species (pigs) more closely related to humans. This study fills gaps in the next steps towards translation of this therapeutic approach to clinic. Upon completion, our Phase II application will aim to support IND-enabling large animal safety studies. Our long-term goal is to develop a product that provides an effective and safe treatment to NF2 patients by treating the underlying disease cause and potentially also a broader cancer patient population who urgently need better therapeutic options.