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NF2 BioSolutions is supporting Dr. Gary Brenner’s lab at Massachusetts General Hospital to develop a bacterio-immunotherapy to treat NF2-associated tumors. This new approach utilizes a cell-based treatment strategy in which live-attenuated – or, in other words, a less toxic – bacteria (Salmonella typhimurium) is directly injected into tumors. Their published preclinical data show that following the 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 (ASC gene).

Click here to watch the 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, in parallel, to save precious time, the biotech Mulberry Therapeutics was formed to prepare the ground for a future human trial.

LAST UPDATE: under Neil Kirby's leadership, Mulberry is working to raise additional funds and 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.

Click here to learn the latest updates: Watch the webinar where Drs. Brenner and Kirby explained their research and update about Mulberry. The second webinar (at the bottom of the page in the following link) is a Q&A: NF2 Drug Development Update: Bacteria-Mediated Immunotherapy – January 14th, 2023

Mulberry is currently raising private funds, so if you are interested in investing in this biotech, please reach out to them at neil@mulberrybio.com

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.

LAST UPDATE: A biotech company worked on raising funds to prepare for a trial but failed. The construct using the ASC gene discovered in this research will be integrated into the genetically modified bacteria of the project above.

NF2 BioSolutions sponsored the pre-clinical NF2 gene addition program at Dr. Kathrin Meyer’s lab in 2019, a top gene therapy laboratory 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 also uses 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 exciting 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. It is currently establishing collaborations with other NF2 labs for these experiments.
LAST UPDATE: The AAV9 viral construct successfully increased Merlin expression in these NF2 and 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 and a xenograft mouse model using intratumoral injections. We successfully showed the expression of merlin in tumor cells, accompanied by reduced tumor growth in the xenograft model.
Pre-IND documents explaining our clinical trial plan were submitted to the FDA. We applied for an NIH grant to fund the preparation of a future trial.

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. NF2 BioSolutions, NF NorthEast, and NF Michigan have partially funded this research program.
LAST UPDATE: The construct was tested on mice at Dr. Clapp's lab at Indiana University and did not show efficacy.

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 also be tested to deliver the ASC gene (See suicide gene above).

LAST UPDATE: Currently, Zhou lab is also characterizing a cell-penetrating antibody for treating NF2. This specific antibody is unique for two reasons. First, the antibody can penetrate tumor cells and promote tumor immunity through cGAS-activation. A preliminary study showed that treatment with this antibody only effectively inhibited the development of intracranial tumors. Second, the antibody can bind and deliver DNA/RNA and thus be employed as a non-viral vector to deliver genetic materials. In this study, the Zhou lab will characterize the effect of intratumoral administration of the antibody carrying NF2 DNA/RNA for NF2 treatment. The treatment is expected to achieve a combination of NF2 gene replacement therapy and immunotherapy effects.

TILs are immune cells that have 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 an individual patient's tumor. Immunological therapies have been demonstrated to be effective in a range of solid and hematological malignancies.

The NF2 BioSolutions Biobank organizes an open and ongoing collection of tissue samples and other biospecimens, including blood and bodily fluids donated by people with NF2. NF2 BioSolutions has developed the Biobank 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 to conduct research. The NF2 BioSolutions Biobank represents the only NF2-specific biobank that aims to increase the availability of NF2 biospecimens. It was established in the Spring of 2022. It will provide researchers with invaluable medical and scientific resources that will help researchers understand how the disease manifests and develop treatments for patients. Additionally, NFBS has partnered with C# Cell Culture Company to create cell lines derived from tissues within the biobank, further expanding the number of avenues for researchers to study NF2.

LAST UPDATE: Currently, the Biobank houses 68 tumor samples and 23 blood tubes. The samples and cell lines collected by the institution that previously held our Biobank are being relocated to Massachusetts. 

This project aims to understand the role of 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 types 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 hypothesizes that targeted immunotherapies in sporadic VS are likely equally efficacious in NF2 VS, opening up new clinical trial opportunities. However, it is also critical to understand how these immune cells interact and behave in the tumors to devise optimal immunotherapeutic strategies, and the team will study this in the coming months.
Three scientific papers were published so far on this project.

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 leads 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 an NF2 spinal cord tumor. NF2 BioSolutions is currently funding this significant effort that we will make available to all NF2 research labs; we hope this will help them tackle this destructive type of tumor. The research is ongoing, but preliminary results are encouraging, showing the possible formation of NF2-type ependymomas in mice.

LAST UPDATE: After 15 months, the mice are being analyzed to determine the characteristics of the tumors. Conclusion expected in winter 2023