Thanks to the unwavering support of our volunteers, ambassadors, and donors we have been able to jumpstart and support the following research initiatives and tools.
Please consider donating to help us continue the fight against NF2 and find a cure for our kids and families.
Bacteriology-immunotherapy: Dr. Brenner’s lab & Dr. Mekalanos’ lab, Mass. General Hospital/ Harvard Medical School (Boston)
NF2 BioSolutions is supporting Dr. Gary Brenner’s lab at Massachusetts General Hospital for the development of bacterio-immunotherapy to treat NF2-associated tumors. This new approach utilizes a cell-based treatment strategy in which live-attenuated – or in other words, less toxic – bacteria (Salmonella typhimurium) are directly injected into tumors. Their published preclinical data show that following injection of these therapies into NF2 schwannomas the tumors shrink and, in some cases, completely resolve.
Currently, Dr. Brenner in collaboration with Dr. John Mekalanos continues to develop genetically modified versions of the Salmonella bacterial product designed to improve efficacy and decrease toxicity. One strategy involves creating bacteria “armed” with genes that enhance tumor cell death.
Here is a webinar where Drs. Brenner and Mekalanos explained their research: https://youtu.be/MnQFTfGXUMU
Developing new strains of bacteria and testing on different mouse colonies is time-consuming, which is why parallel, to save precious time, the biotech Mulberry Therapeutics was formed to prepare the ground for a future human trial.
Mulberry, under the leadership of Neil Kirby, is working to raise additional funds and to move the Salmonella product described in the Brenner/Mekalanos PNAS paper to human clinical trials. Mulberry has significantly de-risked this therapy following a successful pre-IND meeting with the FDA. Mulberry has been granted orphan drug designation for this therapy in the US and Europe and has assembled a world-class internal and external team of advisors with unique expertise in bacterial engineering, tumor biology, and rare disease drug development. Mulberry is collaborating with leading NF2 experts and schwannoma experts to progress the development of this novel therapy and has the support of NF2 BioSolutions and the NF2 patient community. In addition to an STTR grant, Mulberry has raised $2M to date. The goal is to enter clinical trials in 2023 as a targeted therapy for patients with schwannomas associated with NF2.
Mulberry is currently raising private funds, if you are interested in investing in this biotech, please contact firstname.lastname@example.org
Suicide Gene: Dr. Brenner’s lab, Mass. General Hospital/Harvard Medical School (Boston)
NF2 BioSolutions is supporting the lab and research of Dr. Gary Brenner, which aims to accelerate the translation of their gene therapy to clinical trials. Experiments in NF2 mice models have demonstrated the efficacy of the therapy in destroying schwannomas. The team led by Dr. Brenner has designed a gene therapy strategy that uses an adeno-associated (AAV) viral vector that expresses the “cell death” gene ASC to attack the mutated Schwann cells that cause the tumors. Currently, a biotech company is working on raising funds to prepare for a trial. At the same time, they are producing cell lines to support clinical manufacturing of the construct, which is essential for the project to gain investment support. Also, a team is being assembled to design and execute efficacy and toxicology studies; these studies are needed in response to comments from the FDA (pre-IND interview).
Gene Addition: Dr. Meyer’s lab, Center for Therapy Center, Nationwide Children's Hospital (Columbus, OH)
NF2 BioSolutions sponsored the pre-clinical NF2 gene addition program at Dr. Kathrin Meyer’s lab in 2019, a top gene therapy laboratory located at Nationwide Children’s Hospital in Columbus, Ohio. The team consists of gene therapy researcher Dr. Kathrin Meyer, NF2 researcher Dr. Long Sheng Chang, post-doctoral associate Dr. Oksana Pavlyuk, and research assistant Krizelle Alcantara, who is also a member of the NF2 BioSolutions scientific advisory board.
Several viral constructs have been designed and manufactured to insert a healthy copy of the NF2 gene into the cells of NF2 patients. By adding a healthy copy of the NF2 gene, we will restore the production of the NF2 protein product Merlin; if absent, the result is the growth of tumors in the nervous system.
Three cell cultures were developed from the direct conversion of fibroblasts derived from skin cells (of NF2 patients) into induced Schwann cells (iSCs). As expected, Merlin protein levels are reduced in patients' ISCs compared to healthy cells. Dr. Meyer’s research team made “second allele hit” models with these cell lines using shRNA. This "second allele hit" turns the cells into tumor cells. The team is also using CRISPR to knock out the gene to mimic tumor cell situations; the lab is currently characterizing the cells.
In the future, the lab wants to develop more patient ISCs cell lines; the team sees interesting differences between the individual patient iSCs and would like to expand its repertoire of cell lines. The lab is also gearing up to test the ability of these cells to form tumors in vivo in xenograft models, and is currently establishing collaborations with other NF2 labs for these experiments.
The AAV9 viral construct successfully increased Merlin expression in these NF2 cell lines and in HEK293 NF2 cell lines. The AAV9 construct also showed beneficial downstream effects on expression markers related to tumor cells and on cell growth.
The efficacy of this construct is currently undergoing testing. Testing is also ongoing in the KO (Knockout) mouse model, as well as a xenograft mouse model using intratumoral injections. We were able to successfully show the expression of merlin in tumor cells, accompanied by reduced tumor growth in the xenograft model.
Gene Replacement: Dr. Flotte’s lab, University of Massachusetts (Worcester, Massachusetts)
NF2 BioSolutions introduced the NF2 disease challenge to Dr. Mueller who decided to launch a pre-clinical NF2 gene replacement research approach. University Dean Dr. Terry Flotte took over the project, where postdoc Dr. Katharina Meijboom designed the vectors (virus) that will silence the mutated NF2 genes and add a healthy copy. This research program has been partially funded by NF2 BioSolutions, NF NorthEast, NF Michigan.
Currently, the construct is being tested on mice at Dr. Clapp's lab at Indiana University.
Non-viral NF2 Gene Addition: Dr Zhou, Yale School of Medicine, Yale University
An alternative way to deliver a healthy NF2 gene to a cell is to use nanoparticles. Dr. Zhou developed second-generation polymer nanoparticles, initially for transporting the NF1 gene.
NF2 BioSolutions would like to have this gene delivery approach tested on the NF2 gene, and engaged with Dr. Zhou’s lab in spring 2022.
Dr. Zhou’s particles are a stable powder, easy to store, and can release the gene to the cells over time. These particles can deliver DNA, mRNA, and CRISPR.
In mid-2022, Dr. Zhou designed the particle for the NF2 gene and is currently testing it on mouse models.
These particles will be also tested to deliver the ASC gene (See suicide gene above).
NF2 Immunotherapy Tumor-Infiltrating Lymphocytes (TILs)
TILs are a type of immune cell that has moved from the blood into a tumor. Tumor-Infiltrating Lymphocytes (TILs) can recognize and kill cancer cells. In cancer therapy, Tumor-Infiltrating Lymphocytes are removed from a patient’s tumor, grown in large numbers in a laboratory, and then given back to the patient to help the immune system kill the cancer cells. Also called TIL.
Adoptive cell therapy with tumor-infiltrating lymphocytes:
This therapy is based on the infusion of T-cells obtained from the tumor of an individual patient. Immunological therapies have been demonstrated to be an effective treatment in a range of solid and hematological malignancies.
NF2 BioSolutions Biobank: Massachusetts's General Hospital and C3 Cell Culture Company
The NF2 Biobank is an open, ongoing collection of tissue samples and other biospecimens, including blood and bodily fluids donated by people with NF2. The Biobank has been developed by NF2 BioSolutions with the generous support of private donations and grants to accelerate NF2 research.
Because NF2 is a rare disorder, researchers are limited by the lack of available tissue with which to conduct research. Until recently, there have not been any substantial collections of NF2 tissue or body fluids to support ongoing or new research. The NF2 Biobank was established in the Spring of 2022 and will provide researchers with invaluable medical and scientific information that will help understand and treat patients today, and hopefully find better treatments and a cure for NF2 in the future.
NF2 BioBank: Dr. Adam Resnick’s Lab, CBTN at the Children’s Hospital of Philadelphia (CHOP)
Having access to NF2 tumors and NF2 cell lines is a key requirement for labs to progress toward a treatment. NF2 BioSolutions united researchers/clinicians and launched an NF2 Tissue/Cell bank in mid-2020. NF2 BioSolutions is getting NF2 surgeons who remove tumors and research labs that need tumors to participate and benefit from a large number of NF2 tissues/cells. To date, more than 60 patients have consented to donate their NF2 tumor and/or blood samples and/or saliva. More than 15 agreements have been signed between clinics, hospitals, and our NF2 Biobank allowing the transfer of tissue samples and de-identified patient data.
In 2022, NF2 BioSolutions and CBTN worked on collecting the saliva samples of more than 150 people (50 trios, parents+child) in order to perform a full genome sequencing. The raw data has been sent back to CBTN for analysis. The analyzed data will be accessible online by researchers through the ”NIH Kids First Program”
Biobank head Dr. Adam Resnisk said; “NF2 BioSolutions is a real leader across the rare disease landscape in how we address the challenges of drug discovery and accelerate impact for patients”.
Recently, in order to speed up the sharing of the bio tissues, ownership of the samples is being transferred to NF2 BioSolutions. Please contact us so we can access the tissues from your past surgeries or plan the tissue donation for your next surgery. Visit our webpage: https://nf2biosolutions.org/nf2-biosolutions-biobank/
Here is a webinar where Dr. Resnick explained the NF2 Biobank: https://youtu.be/-RhtOyEnakg
Inflammation in NF2 tumor and therapeutic targets: Geoffrey Jefferson Brain Research Centre, Manchester. Prof David Brough, Prof Kevin Couper, Prof Omar Pathmanaban and Dr Pawel Paszek. Grace Gregory and Adam Jones.
The goal of this project is to understand the role of the inflammation in the NF2 vestibular schwannomas and meningiomas, how it is linked to tumor growth and how we could control the growth. This project started in 2021 and the team discovered that the microenvironment (different type of cells) of vestibular schwannomas from non-NF2 patients appear to be very similar to the NF2 patients’ vestibular schwannomas. This comparison is being validated using high dimensional imaging, which will study the types of cells that exist in the tumor, including granulocytes, B cells, T cells, macrophages and monocytes. The team hypotheses that targeted immunotherapies in sporadic VS are likely to be equally effective in NF2 VS, which opens up new opportunities for clinical trials. However, it is also critical to gain understanding of how these immune cells interact and behave in the tumours to devise optimal immunotherapeutic strategies, and the team will study this in the coming months.
Vestibular Schwannoma modeling and 3D volumetric: Dr Wiznia and Dr Buono, Yale University
For NF2 patients and clinicians, it is very important to know the accurate size of the NF2 tumors, to know whether they are stable or growing. If they are growing, it is important to know and their growth rate, since the patients sometimes have small windows of opportunity for surgery and radiation. This is especially true for the vestibular schwannomas that are endangering the hearing, balance and facial nerve function. Today, most patients don’t have access to accurate volumetric measurement of the vestibular schwannomas, because it is time consuming for the radiologist and expensive.
The goal of this study is to automate accurate volumetric measurements of the vestibular schwannomas, and to have a 3D visualization of the vestibular schwannomas in order to see which areas of the tumor is growing. NF2 BioSolutions jumpstarted this project thanks to a donation from one anonymous generous donor.
Three patients’ sets of MRI have been used for a proof of concept study, and now more MRIs are being collected from NF2 patients to automate the volume calculation, using artificial intelligence machine learning.
Here is an example of a patient 3D Vestibular schwannoma modelling. The yellow areas are the parts of the tumor that grew over a 1 year period.
Ependymoma mice model: Dr. Kalamarides lab, Pitié-Salpêtrière Hospital(Paris, France)
Spinal ependymomas are the third most frequent tumor type in NF2. They are located within the spinal cord, predominantly at the cervical level. The growth of ependymomas is unpredictable and sometimes very fast and lead to pain, paralysis and even death.
The goal of this new research program at the laboratory of Professor Michel Kalamarides is to develop a new mouse model for ependymoma that recapitulates the features of human NF2 spinal ependymomas; namely the same histological aspect, same cell of origin, same growth patterns. This will hopefully allow the preclinical evaluation of therapeutic interventions such as medical treatment or gene therapy approaches as advocated by NF2 Biosolutions. This model will be the first mouse model of a NF2 spinal cord tumor. NF2 BioSolutions is currently funding this very important effort that we will make available to all NF2 research labs; it is our hope that this will help them tackle this destructive type of tumor. The research development is still ongoing, but preliminary results are encouraging, showing the possible formation of NF2 type ependymomas in mice.
These achievements were done thanks to the donations to NF2 BioSolutions. NF2 BioSolutions, is a patient volunteer-run, nonprofit organization that effects change through patient advocacy by bringing the smartest minds in various research fields together to find an NF2 treatment or cure.