GT-02287 Helps Prevent Toxic Alpha-synuclein in Patient-derived Cells

Experimental Parkinson's treatment still showing disease-modifying potential

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Parkinson's progression | Parkinson's News Today | trial data presentation illustration

GT-02287, Gain Therapeutics’ experimental oral therapy, reduced the toxic alpha-synuclein protein clumps that characterize Parkinson’s disease in lab-grown nerve cells derived from patients with disease-causing mutations in the GBA1 gene, the company announced.

The treatment also boosted the function of lysosomes, the cells’ recycling centers, which is affected by GBA1 mutations.

These findings add to a growing body of evidence showing GT-02287 treatment results in beneficial effects in mouse and cell models of Parkinson’s.

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“We are especially excited by these latest data because they were generated in a model that replicates Parkinson’s disease in patient-derived cells,” Matthias Alder, CEO of Gain, said in a company press release.

Manolo Bellotto, PhD, Gain’s chief strategy officer and general manager, discussed the findings in the presentation “Non-inhibitory Chaperones for GBA-Parkinson’s Disease,” given at the Shaare Zedek Medical Center GBA Parkinson’s disease symposium in Jerusalem.

Mutations in the GBA1 gene are present in approximately 14% of Parkinson’s patients, representing the most common genetic risk factor for the disease. People carrying these mutations have earlier disease onset and faster progression.

Small molecule therapy designed to reach the brain and spinal cord

The GBA1 gene provides instructions to produce beta-glucocerebrosidase (GCase), an enzyme critical for lysosomal function and whose deficiency or dysfunction causes molecules to accumulate to toxic levels inside cells.

Low GCase activity is common among Parkinson’s patients with no known disease-causing mutations, and it is thought to contribute to the buildup of the toxic alpha-synuclein protein that ultimately damages patients’ nerve cells.

GT-02287, Gain’s lead candidate for treating Parkinson’s, is a small molecule designed to bind to and promote the proper folding of the GCase enzyme, thereby boosting its activity.

It can cross the blood-brain barrier, a highly selective membrane that tightly regulates what substances from the bloodstream can access the brain and spinal cord.

As such, the therapy is expected to lower the toxic accumulation of alpha-synuclein and protect against — and possibly reverse — nerve cell damage in Parkinson’s patients with or without GBA1 mutations.

Belonging to a class of molecules called structurally targeted allosteric regulators (STARs), the therapy was developed using the company’s Site-directed Enzyme Enhancement Therapy system. That system uses a three-dimensional structure of a target enzyme to predict how it might interact with therapeutic compounds.

A number of preclinical studies have demonstrated GT-02287’s therapeutic potential for Parkinson’s.

In animal models of the disease, it was shown to reduce alpha-synuclein buildup, lower inflammation, ease behavior problems, and improve fine motor skills in a dose-dependent manner. Fine motor skills help in using the smaller muscle of the paws or, for people, the hands.

In lab-grown human nerve cells engineered to carry GBA1 mutations, the experimental treatment likewise lowered the accumulation of alpha-synuclein clumps, improved lysosomal function, and supported nerve cell health and function.

The newly presented data concerned a study that used a nerve cell model derived from induced pluripotent stem cells (iPSCs) taken from Parkinson’s patients with GBA1 mutations.

iPSCs are generated from fully matured cells, such as those in the skin or blood, that are reprogrammed back to a stem cell-like state where they can give rise to almost every type of human cell. As such, when derived directly from patients, they can be used as “disease in a dish” cellular models that mimic the disease’s genetic and clinical diversity.

These patient-derived iPSCs were grown in the lab and matured into dopamine-producing neurons, the nerve cells primarily affected in Parkinson’s.

When these cells were treated with GT-02287, significant and positive effects were observed across a range of parameters. These included an increase in GCase levels and in its transport to the lysosomes, where it exerts its action. The levels of toxic alpha-synuclein clumps also were reduced.

These findings were consistent with those previously reported with iPSCs from people with Gaucher disease, a condition marked by GCase deficiency due to GBA1 mutations.

“The consistency and strength of these latest data not only support our earlier findings in iPSC-derived neuronal cells from [nerve damaging] Gaucher Disease patients, but, more importantly, offer further compelling evidence of the disease-modifying potential and unique mechanism of action of our approach,” Alder said.