Gene Replacement Therapy for Neurofibromatosis 1-Related Tumors with AAV Virus
Abstract
Neurofibromatosis type 1 (NF-1) is a genetic disease where patients are at high risk for developing cancers, particularly cancers arising from peripheral nerves termed malignant peripheral nerve sheath tumors (MPNSTs). Although MPNSTs develop only in 8 to 13% of NF1 patients, they represent the number one cause of mortality in adults younger than 40 years. Unfortunately, this highly aggressive cancer is very difficult to treat and largely considered incurable, despite aggressive surgery, chemotherapies, and radiation, as well as intensive research efforts to identify new drugs. One largely unexplored treatment area for these tumors is gene therapy, i.e., the therapeutic delivery of genetic material into the cancer cells using a virus, with the goal of restoring normal cell activity and stopping cancer growth. Indeed, NF-1-associated MPNSTs would be perfect candidates for such a therapy because all MPNSTs share the same genetic abnormality that gives rise to tumor development, and repairing this genetic defect could, in theory, result in tumor shrinkage and even cure. Although the concept of replacing a malfunctioning gene sounds simple, gene therapy has been complicated by a number of technical difficulties in the past, mainly related to safety and efficacy concerns regarding viral delivery, but those have now been resolved with the development of even more effective and safer virus delivery methods. Our preliminary data show that such an approach is feasible and effective in stopping the growth of MPNST cells derived from various NF-1 patients. Encouraged by these results, we are therefore proposing to develop a virus-based gene therapy that is specifically selected and optimized for use against MPNSTs in NF-1 patients. Furthermore, we aim to obtain the preclinical data to support a future clinical trial, including developing this therapy in a special mouse model with a human MPNST and a human immune system. Finally, we will take advantage of imaging techniques to monitor the distribution and effectiveness of this therapy in the body, which will ultimately aid in moving this therapy to the clinic for treatment of this currently incurable, tragic disease. If our work is sufficiently funded and successful, we expect to have an optimized virus that can be tested for safety in NF-1 patients with MPNSTs in approximately 3 to 5 years of work. Notably, this would be the first treatment for NF-1 patients that would aim to “correct” the molecular cause of these tumors and reach far beyond what can be achieved with conventional anti-cancer drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810236
Entities
People
- Renyuan Bai
Organizations
- Johns Hopkins University
- United States Army