GM2 Gangliosidosis (GM2-g)
GM2 gangliosidosis is characterized by the progressive destruction of nerve cells in the brain and spinal cord, leading to severe neurological impairments. The most common form of GM2-g typically manifests in infancy, but some variants can present in childhood, adolescence, or even adulthood. Our company is committed to contributing to this field through ongoing research, innovation, and collaboration with experts in the field.
Introduction to GM2-g
GM2 gangliosidosis, also known as GM2-g, is a rare genetic disorder that affects the nervous system. The incidence of GM2-g is approximately 1-9/100 000. GM2-g arises from mutations in either the HEXA or GM2A gene, which disrupt the normal activity of an enzyme called beta-hexosaminidase A. This enzyme is responsible for breaking down large molecules inside cells, particularly GM2-g, a fatty substance that plays a crucial role in cell signaling and maintenance. Undigested GM2-g accumulates primarily in the brain, including neurons, microglia, and glial cells. This accumulation leads to progressive damage to nerve cells and severe nerve damage.
Fig.1 Physiopathological events in GM2 gangliosidoses. (Leal, Andrés Felipe, et al., 2020)Animal Models of GM2-g
While GM2 gangliosidosis has been observed in various species, mice, cats, and sheep are the primary research models utilized.
- Mouse: The GM2-g mice model, known as HEXA knockout, exhibited characteristic disease features predominantly in specific brain areas such as the septal area, hippocampus, and cerebral cortex. The GM2 activator deficiency mouse model had intermediate characteristics, including cerebellar pathology and motor deficiencies, but did not exhibit a reduced lifespan.
- Cat: In cats, GM2-g disease-associated mutations have been identified in various breeds, including European Burmese, Korat, domestic short-haired cats, and Japanese domestic cats. These cats exhibit extremely low levels of Hex enzyme activity (less than 3% of normal) and reduced protein levels (approximately 15% of normal) due to a 25-base pair inversion at the coding sequence's 3' terminus. This mutation results in antigenically cross-reactive material, potentially affecting the immune response to therapeutic protein.
- Sheep: The Jacob breed provides a suitable model for GM2-g disease research. These sheep exhibit noticeable clinical signs and have a larger brain size, making them easily maintainable in a research setting. The disease in these sheep is caused by a single base substitution in the HEXA gene, resulting in a glycine to arginine substitution in the α subunit and a significant decrease in HexA activity.
Therapeutics Development of GM2-g
Enzyme Replacement Therapy
Enzyme replacement therapy (ERT) is a therapeutic approach that involves delivering lysosomal enzymes to the lysosomes through endocytosis. Fusion proteins known as molecular Trojan horses have been developed. These fused proteins, such as HexA fused to a monoclonal antibody (MAb) that recognizes either the human insulin receptor (HIR) or the transferrin receptor (TfR), have shown promising results in non-human primate studies.
Hematopoietic Stem Cell Transplantation
Lentiviral vector-mediated gene therapy is a promising approach, increasing Hex activity without affecting stem cell functions. Overcoming graft-versus-host disease remains a challenge, but hypoimmunogenic human stem cells or autologous HSCT could offer solutions.
Pharmacological Chaperones
Pharmacological chaperones (PCs) are small molecules that can bind to target proteins, stabilizing their native conformation or promoting correct folding. In the case of GM2-g, PCs have been investigated as potential therapeutic agents. One such PC, pyrimethamine (PYR), has shown promising results in increasing enzyme activity.
Our Services
We understand the complexities and challenges associated with rare diseases, and our team of experts is dedicated to providing innovative solutions and tailored approaches for the development of effective therapies for GM2-g and other rare genetic diseases.
- GM2-g Diagnostic Development Services: For rare genetic diseases such as GM2-g, our company offers diagnostic development services and state-of-the-art Next-Generation Sequencing (NGS) products. We are dedicated to assisting you in the development of rapid and point-of-care diagnostic tests for GM2-g, ensuring accurate and timely detection.
- GM2-g Therapeutic Development Services: Our services extend beyond diagnostics, and we are also committed to the development of novel therapeutics for rare diseases. Our company provides a wide range of services for the development of small molecule drug, cell therapy, gene therapy, therapeutic antibody, therapeutic peptide, and therapeutic protein. We have extensive experience in the development of fusion proteins for GM2-g enzyme replacement therapy and the use of lentiviral vectors for gene therapy.
- GM2-g Animal Model Service: To support the preclinical research and development of GM2-g therapies, we offer GM2-g animal model services, including HEXA knockout mice, cats with GM2-g disease-related symptoms, and sheep with HEXA base substitutions to support your pharmacokinetics study and drug safety evaluation.
If you are interested in our services or require further information, please contact us, and our team will be happy to assist you.
Reference
- Leal, Andrés Felipe, et al. "GM2 gangliosidoses: clinical features, pathophysiological aspects, and current therapies." International journal of molecular sciences 21.17 (2020): 6213.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
