AAV-mediated delivery of the inflammasome adapter protein, ASC, as a pro-apoptotic gene therapy for schwannoma

SUMMARY Schwannomas are slow-growing non-malignant tumors that grow along peripheral, spinal, and cranial nerves. Schwannomas may arise sporadically or as part of the debilitating genetic syndromes NF2-related schwannomatosis (NF2-SWN) and schwannomatosis. In approximately 60% of individuals with schwannoma- associated disease, tumors initially appear in childhood and young adulthood, with new lesions continuing to form in multiple locations throughout life. These schwannomas can cause deafness, loss of vision, disorders of balance, severe and persistent pain, substantial psychological co-morbidity, and may even lead to death. While schwannomas initially present as benign and non-invasive tumors, they carry the potential to develop into malignant peripheral nerve sheath tumors. Current treatment is limited to surgical resection, which carries significant risks and is not always feasible. There are no pharmacological therapeutics currently available that address the underlying genetic cause of these tumors. Schwannomas are appealing targets for gene therapy, as they are slow growing and can be localized using magnetic resonance imaging. We have previously described a gene therapy that targeted schwannomas using an adeno-associated virus serotype 1 (AAV1) vector expressing the pro-apoptotic inflammasome adapter ASC gene under the control of the Schwann-lineage cell-specific promoter P0. ASC is a protein with pro-apoptotic and pro-inflammatory functions, which makes it a prime candidate for eliminating schwannoma cells as this single transgene has the potential to induce apoptotic cell death and cell growth cycle arrest in the cells in which it is expressed. Merlin Therapeutics is now furthering the development of this gene therapy, termed MRL-102, as a targeted treatment for schwannoma. Our previous studies have demonstrated that MRL-102 (1) is highly effective at eliminating schwannoma tumor cells with minimal toxicity and (2) diminishes tumor-associated pain in schwannoma mouse models. We have completed an FDA INTERACT meeting to establish our path to an IND application. We now propose work that is necessary to support the IND filing; we will advance toward clinical translation of our therapy by developing a scalable manufacturing process for cGMP MRL-102 production, developing analytical methods, and performing efficacy and toxicity bridging studies in additional mouse models, with the goal of developing a complete pre- IND submission package to seek additional FDA guidance and concurrence on Merlin’s clinical development plan for MRL-102. If successful, this mission-critical work will position Merlin Therapeutics to file an IND in order to move forward with first-in-human studies. The completion of this project will bring us one step closer to providing life- changing treatments to patients with schwannomas.