Gain is establishing a new perspective of medical treatments for diseases that have been historically seen as undruggable with its Site-Directed Enzyme Enhancement Therapy (SEE-Tx) platform, a proprietary computational approach to rapidly and effectively identify allosteric binding sites on enzymes that have never been targeted previously.

Gain’s approach is built on extensive and unique knowledge of high-power molecular modelling, generated through multi-year research activity. SEE-Tx works by using the 3D structure of proteins and proprietary computational technology to replicate the natural phenomena on the computer (or in silico). After discovering a new allosteric binding site, the platform quickly scans through millions of small molecule drugs that can bind to that site and guide proteins back to their proper shape. This facilitates a highly specific, efficient and cost-effective drug discovery approach that has a ~10% success rate, up to 1,000 times higher than traditional high throughput screening methods.

These small molecules are called Structurally Targeted Allosteric Regulators (STARs). They are orally deliverable, able to reach organs and tissues not accessible via current therapeutic options, and are easy to manufacture. In addition to binding allosteric sites to correct misfolding in mutant enzymes, STARs can potentially protect and enhance normal enzyme activity.

SEE-Tx not only has the ability to help enzymes gain function, but can also help induce a loss of function, which can be potentially beneficial in the treatment of some cancers. This novel approach distinguishes Gain in the field of oncology. In April, Gain announced a multi-target collaboration agreement with Zentalis Pharmaceuticals to discover new product candidates for the treatment of some cancers. The intended output is newly discovered targets or target protein interactions that can then be drugged for therapeutic benefit to intervene with potential protein misfolding. Gain will focus on binding site identification on target proteins with its SEE-Tx platform technology, that will then be selected and agreed upon by both companies. Gain also plans to identify and determine the potential suitability of these sites as drug targets, as well as their prospective therapeutic use. Selected compounds will be tested in the lab by Zentalis against the target protein to confirm binding and action to identify and characterise novel compounds for development and clinical evaluation.

Outside oncology, Gain strategically selected its first indications by initially targeting rare diseases that share a genetic profile with a larger, more prevalent indication such as Gaucher’s disease and Parkinson’s disease. Current indications of focus include GM1 Gangliosidosis, Morquio B, neuronopathic Gaucher disease (nGD), GBA1 Parkinson’s disease (GBA+PD), Krabbe disease and Mucopolysaccharidosis type 1 (MPS 1).
With its GM1 Gangliosidosis and Morquio B programs, Gain is investigating the restoration of beta-galactosidase. GM1 Gangliosidosis is a hereditary, progressive disease mostly impacting neurons in the brain and spinal cord while Morquio B, also known as Mucopolysaccharidosis type IV (MPS IV), is a progressive disease mostly impacting the skeleton. Both are caused by mutations in GLB1, the gene that encodes the beta-galactosidase (GLB) enzyme. Gain has developed lead compounds that can be orally delivered for the treatment of these diseases. With GM1 patient-derived fibroblasts in preclinical studies to date, these lead compounds demonstrated reduction in accumulation of GM1 ganglioside substrate. It was also demonstrated that the compounds were able to cross the blood-brain-barrier in vivo as well as penetrate bone tissue. Gain is currently completing IND-enabling animal studies for GM1 Gangliosidosis, and results are expected within the year.

In nGD and GBA+PD, Gain is investigating restoration of beta-glucocerebrosidase (GCase) function. nGD is the most common lysosomal storage disease while Parkinson’s is a neurodegenerative disorder that affects more than six million people worldwide. Mutations in GBA, the gene that encodes the GCase enzyme, is the cause of nGD and though the exact cause of Parkinson’s is unknown, its mutation has been tied to the progression of GBA+PD in up to 10% of all Parkinson’s patients. In May, Gain announced positive preclinical data that showed the company’s platform technology was able to successfully identify two STAR compounds that increased GCase activity and decreased toxic substrate accumulation (alpha synuclein) in neuronal and patient-derived cell lines. This opens a new potential approach for direct treatment of GBA+PD.

For Krabbe disease, Gain is investigating the restoration of GALC, the gene that encodes the galactosylceramidase (GALC) enzyme. Krabbe disease is a severe neurodegenerative disorder associated with demyelination. In preclinical studies to date, Gain’s STAR compounds demonstrated ability to stabilize galactosylceramide and enhance its activity in WT cells. Ongoing studies will optimise a lead compound and progress into animal models.

Finally, in MPS 1, Gain is investigating restoration of alpha-L-iduronidase (IDUA). MPS 1 is a rare lysosomal storage disease that is caused by mutations in IDUA, the gene that encodes the IDUA enzyme. In preclinical studies, Gain is currently investigating the development of allosteric regulators to increase IDUA activity and decrease toxic sugar accumulation in the CNS of patients with MPS 1 to potentially become the first treatment for the disease’s neuronopathic symptoms.

In addition to the company’s recent collaboration with Zentalis Pharmaceuticals to investigate novel oncology candidates, Gain has received initial validation of its unique computational approach through other key partnerships and grants. Gain has established a partnership with Sumitomo Dainippon Pharma Co Ltd which will focus on the research and development of STARs to restore functional activity of defective lysosomal enzymes for rare genetic and demyelinating diseases.

Gain has also received funding from the Michael J. Fox Foundation and the Silverstein Foundation for the discovery and development of its lead compounds for Parkinson’s disease. Additional funding sources include Eurostars and InnoSuisse. With these established relationships. as well as the ability to utilise innovative computational biology, Gain hopes to bring life-saving medicines to those with these devastating disorders.

Eric Richman is CEO of Gain Therapeutics