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RESEARCH SUMMARY
Since 2007, the New Hope Research Foundation has coordinated and funded numerous research projects investigating options for treating the central nervous system (CNS) aspects of lysosomal storage diseases. The focus of these studies have been finding treatments for GM2 gangliosidosis, a disease that primarily affects the CNS. It is the hope that the discovery of general methods for treating this disease could be utilized in the future for other diseases that affect the CNS.
Pharmacological Chaperone Therapy
Early studies funded by the Foundation investigated a small molecule drug, called pyrimethamine, which is known to cross the blood brain barrier (BBB) and enter the brain. This oral drug has been approved by the US Food and Drug Administration for over a half century for the treatment of malaria and toxoplasmosis. It has been recently shown in the laboratory to aid in the stability of the hexosaminidase enzyme, which functions to break down GM2 ganglioside. Clinical studies, funded by the New Hope Research Foundation, have shown that pyrimethamine serves as a pharmacological chaperone for the hexosaminidase enzyme and that pyrimethamine is thereby able to increase the level of the enzyme in Adult Tay-Sachs disease patients that express an unstable form of this enzyme. More information on the pyrimethamine clinical study results was published by Clarke et al. (2011) and in a case study presented by Keimel and Charnas (2009) and by Keimel (2010).
Gene Therapy
Gene therapy has the greatest potential for curing GM2 gangliosidosis and other lysosomal storage diseases that affect the CNS. Three major challenges associated with gene therapy relate to the effective delivery of large genetic material into deficient cells, to the need for adequately distributing the gene vector throughout the CNS, and in avoiding an immune response to the protein expressed by the gene vector. The gene therapy research being conducted by the Foundation has focused on responding to these challenges.
Biodistribution: Early gene therapy clinical studies used a method of directly injecting the vector into the brain tissue, but the vector does not distribute very far from the site of injection and the volume of tissue transduced with this method is extremely limited. This method is only practical in small animal brains. The New Hope Research Foundation has focused its research on gene transfer delivery methods that will result in broad delivery of the gene vector throughout the CNS. The Foundation has identified methods for gene delivery, and is currently conducting investigations to delineate the vector distribution within the body, and in particular, the CNS. A future research project to evaluate these delivery methods in large animals is planned.
HexM: Research funded by the Foundation has also resulted in the development of a new enzyme, called HexM, licensed to the Foundation (US Patent 10,400,227). The advantage of HexM is that the complete gene can be packaged in one small adeno-associated virus (AAV) capsid (Foundation assigned US Patent 10,016,514). Incorporating the complete genetic material into a single small package has been shown to enhance the CNS biodistribution and also increase the efficiency of the vector.
Extensive investigations have been completed that confirm the function of the new variant hexosaminidase enzyme, HexM, in effectively degrading the GM2 ganglioside within cell culture (Tropak et al., 2016 and Tropak et al., Supplement, 2016). The initial in vivo gene therapy research using this new enzyme in neonatal mice was presented at the 2015 annual meeting of the American Society for Gene and Cell Therapy (ASGCT) by Karumuthil Melethil et al., 2015, and Osmon et al., 2015. It was also summarized in a poster presented by Keimel et al., 2015, at the annual meeting of the Institute for Engineering in Medicine. This research not only established that the enzyme is effective in degrading GM2 ganglioside in mouse models of Tay-Sachs and Sandhoff disease, but also demonstrated that the treatment allowed significant improvements in both the behavioral testing and longevity of the diseased mice. Details of these studies have been published by Karumuthil Melethil et al., 2016 (and Karumuthil Melethil et al., Supplement, 2016), and by Osmon et al., 2016. The gene vector expressing HexM has also been shownto be effective after treating adult mice with either an intravenous injection (Osmon et al., ASGCT 2016) or by an injection into cerebrospinal fluid (Thompson et al., ASGCT 2016). A key result from these studies is the evidence that the AAV vector is able to cross the mature blood-brain-barrier and transduce cells within the CNS. These studies also showed that the gene transfer resulted in significantly improved behavioral performance and increased longevity when the therapy is injected into adult mice. However, as shown by these studies and by other gene therapy studies and during clinical trials, large doses of intravenous delivered AAV can be toxic (Osmon et al., 2021).
To avoid potential toxicity caused by large intravenous delivered doses, the foundation conducted studies on delivering a portion of the total dose directly into the CNS. These studies delivered the total vector dose through either intravenous or intrathecal or both routes. The delivery utilized a novel method intended to osmotically induce the flow of the gene therapy vector into the CNS (Foundation assigned US Patents 11,541,005 and 11,723,865). This study showed that delivering a portion of the total dose directly into the CNS not only reduced the amount of vector being delivered intravenously but also showed a therapeutic benefit of improved survival (Quinville et al, ESGCT 2023, Quinville et al., ASGCT 2024) The study showed that the GM2 gangliosidosis mice in the cohorts receiving the high dose were indistinguishable from normal mice in terms of survival and behavioral assessments – essentially curing the mice of the disease.
Immune Tolerance: The human immune system naturally responds with strong defenses to the invasion of “foreign” substances. Critical to this function is the ability to distinguish these foreign invaders from the body’s own proteins and cells, referred to as “self”. It is anticipated that patients with mutations resulting in no expression of a hexosaminidase gene are expected to have an immune response following the introduction of the enzyme through enzyme replacement therapy (ERT) or to the expression of the enzyme following gene transfer.
Assays have been developed that allow the measurement of anti-HexM antibodies and HexM specific T-cells, which could proliferate following a gene therapy. The research funded by the Foundation has assessed the immune response to the HexM gene transfer in Tay-Sachs and Sandhoff mice (Karumuthil-Melethil et al., ASGCT 2017 and Kot et al., ASGCT 2017), which indicate that immune responses could be impacting the effectiveness of HexM gene therapy expressing the human HexM enzyme in these mice.
To potentially counter this immune response possibility, a method of inducing immune tolerance has been developed and shown to be effective in Sandhoff mice treated with the HexM gene transfer (Keimel et al., IEM 2018).
RESEARCH PLAN AND REQUEST FOR PROPOSALS
The New Hope Research Foundation is generally requesting additional proposals (See Grants) that support research efforts that will lead to the creation of a gene therapy for GM2 gangliosidosis. The most recent requests for proposals can be found at the bottom of the following list: