Research Initiatives

Below are summaries of the research projects we support :

Schwannoma Gene Therapy Project

Schwannoma background:

Schwannomas are benign tumors composed of Schwann-lineage cells that normally form a protective sheath around nerves in the cranium (skull) and peripheral nervous system. Most people with schwannoma-associated disease have multiple tumors which generally first appear during adolescence and continue to develop throughout life.  These tumors cause pain, sensory/motor dysfunction, and death through compression of peripheral nerves, the spinal cord, and/or the brain stem. Effective chemotherapy is essentially non-existent, but because schwannomas are slow growing and non-malignant, reduction in volume and slowing of growth can be therapeutic.  Although it is the current standard of care, surgery and radiation can lead to significant sensory loss (including deafness in the case of vestibular schwannoma) and motor dysfunction, and are not always possible due to the risk of nerve or brain stem damage.  The paucity of therapeutic options, and the suffering caused by what limited options do exist, makes the treatment of schwannomas a major unmet medical need.

Market size:

Schwannomas are associated with three distinct disease entities – sporadic schwannoma, neurofibromatosis type 2 (NF2), and schwannomatosis. Sporadic vestibular schwannomas are diagnosed in over 6000 individuals per year in the US alone (19 tumors/1,000,000 individuals per year). NF2 and Schwanommatosis have incidences of 1/25,000 and 1/40,000 births, with estimated point prevalences (people currently living with the disorder) of 13,000 and 8,000 respectively in the US.

Gene therapy approach:

The focus of the lab is to address this need by developing a gene therapy that specifically targets schwannomas, which are composed entirely of Schwann-lineage tumor cells. Schwannomas are appropriate targets for gene therapy because they grow slowly, are rarely malignant and never metastatic.  They can be readily localized and followed over time using MRI. In addition, tumor genomes have been shown to be stable, with little genomic variability among tumor cells. The advantage of gene-therapy over surgical resection is that the former uses a minimally invasive procedure (image guided needle injection) with significantly less potential for nerve damage.

The team designed a gene therapy strategy that uses an adeno-associated (AAV) viral vector that expresses the pro-apoptotic gene ASC (ASC =“apoptosis-associated speck-like protein containing a carboxy-terminal CARD”) under the Schwann-lineage specific promoter, P0. This novel vector is thus termed “AAV-P0-ASC.” AAV vectors have been shown to be safe for use in the human nervous system in gene therapy trials. The delivery of ASC to schwannoma cells is attractive as ASC is both pro-apoptotic and pro-inflammatory. This gene therapy strategy utilizes a single transgene that potentially can: 1) induce apoptotic cell death in the cells in which it is expressed, 2) propagate the death signal to adjacent tumor cells, and 3) initiate innate and adaptive immune responses that control subsequent tumor formation.

Data obtained using a human-NF2 xenograft model (in immune deficient nude mice) that the team developed to test potential schwannoma therapies indicate that the AAV-P0-ASC vector is very effective in killing schwannoma tumor cells while causing minimal toxicity to underlying neurons and healthy Schwann cells. Notably, the mouse models also demonstrate resolution of tumor-associated pain. There is minimal risk of toxicity with this approach because the P0 promoter is Schwann cell specific and is active only in dividing schwannoma cells while remaining relatively inactive in healthy neighboring Schwann cells.  Of note, these findings have confirmed the AAV-P0-ASC efficacy signal in a second model, this involving mouse schwannomas developing in immune-competent animals.

This program is ready to move to humans.  We believe the researchers have all the data necessary to support moving to human clinical trials. Your support will help us bring this research to those who need it.  

This project is based on many years of research: Regression of Schwannomas Induced by Adeno-Associated Virus-Mediated Delivery of Caspase-1

More papers will be published soon regarding this specific scientific gene therapy approach for schwannomas.

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