Below are summaries of the research projects we support and accelerate:
Gene Replacement Approach:
Thanks to our 29th March 2019 consortium in Boston, we are collaborating with three top gene therapy labs to explore different gene replacement approaches:
1. Dr Meyer Lab at Abigail Wexner Research Institute at Nationwide Children’s Hospital
NF2 BioSolutions signed a contract in July 2019 to partially fund a NF2 Gene therapy Pilot Pre-Clinical Study at the Abigail Wexner Research Institute at Nationwide Children’s Hospital by Dr. Kathrin Meyer, who is serving as the Principal Investigator.
2. Dr Chris Mueller Lab at University of Massachusetts
Dr. Chris Mueller from UMass attended NF2 BioSolutions’s NF2 Gene Therapy ￼Consortium in Boston on March 29th. Being moved by the impact of NF2, Dr. Mueller decided to run a gene therapy pilot study to identify if his lab’s gene therapy platform could be a good candidate for tackling the NF2 mutation. The advantage of his platform is its ability to silence the mutated gene and then add a healthy one. Dr Mueller, assisted by Dr. Karin Meijboom, will be financing the development of the gene therapy NF2 vector for the pilot. Once manufactured, it will be tested on NF2 in order to determine efficacy.
NF2 BioSolutions will facilitate the collaboration between the NF2 experts and the Mueller’s lab.
On the 7th of august 2019, NF2 BioSolutions and NF North East organised a visit to the lab, where NF2 patient could meet the researchers.
Dr. Karin Meijboom “Our recent visit with the NF2 community was an invaluable experience for the Mueller Lab. Not only was it an opportunity to meet with a remarkable and dedicated group of individuals, but we were also fortunate enough to hear, first-hand, their personal stories about living with NF2. As researchers, it is often far too easy for us to focus on the technical mechanisms of a disease, but this visit gave us something more: the inspiration and energy to find solutions and treatments from the inspiring people living with this condition.”
Therapeutic strategy: Gene replacement
To introduce new copies of the NF2 gene using AAV in order to increase the amount of normal NF2 gene product (Merlin) to a level at which it can execute its tumor suppressor functions in patients. This project involves an international collaboration among several research groups with expertise in either NF2 or gene therapy. The Mueller group will design the project and the gene therapy and do preliminary testing in cells and healthy mice. Other groups that have more expertise in NF2 will treat NF2 mouse models with the gene therapy and examine effects on NF2 pathology.
3. Dr Brenner Lab at Massachusetts General Hospital-
Schwannoma Suicide Gene Therapy Approach
NF2 BioSolutions is supporting Dr. Gary Brenner’s lab to move towards a toxicology study prior to submitting an IND (investigational new drug) application to the FDA.
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.
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 Schwannomatosis 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 from Dr Brenner:
More papers will be published soon regarding this specific scientific gene therapy approach for schwannomas.