Small Molecules, STARs Treat Cell Models of GBA1-linked Parkinson’s

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of cells in a petri dish.

Two investigational small molecules known as GT-02287 and GT-02329 lowered toxic protein levels in patient-derived cell models of Parkinson’s disease associated with a mutation in GBA1, their developer, Gain Therapeutics, announced.

Gain is planning additional preclinical studies this year that could support applications to regulatory agencies allowing the compounds to be tested in people, the company’s CEO, Eric Richman, said in a press release.

“These data are extremely exciting, as it further demonstrates the potential of GT-02287 and GT-02329 and expands the body of evidence supporting our … drug discovery platform,” Richman said.

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The GBA1 gene provides instructions for making a protein called beta-glucocerebrosidase or GCase. This enzyme plays a crucial role in the function of lysosomes — cellular compartments that act as “recycling factories,” breaking complex molecules down into simpler substances that can be repurposed by the cell.

Mutations in GBA1 can affect the GCase protein, leading toxic molecules to accumulate in cells that can contribute to Parkinson’s development. The buildup of a protein called phosphorylated alpha-synuclein is especially associated with Parkinson’s. Mutations in GBA1 are also a known cause of Gaucher disease.

GT-02287 and GT-02329 belong to a class of molecules called small-molecule structurally targeted allosteric regulators, or STARs. They work by attaching to the GCase protein and helping it to fold correctly: faulty proteins are typically the result of abnormal folding, since proteins need a very specific shape to do their job properly.

Researchers evaluated these STARs in induced pluripotent stem cell (iPSC)-derived models. iPSCs are stem cells that are “reverse engineered” from other cells in the body, usually skin cells. Like other types of stem cells, iPSCs are able to grow into different kinds of cells if given the right biochemical cues.

In this case, the researchers took iPSCs from people with GBA1-associated Parkinson’s or Gaucher disease, and cued them to become the cells mainly affected in the relevant disease. For Parkinson’s, the cells were engineered into dopaminergic neurons (nerve cells that make the signaling molecule dopamine), as this disease is caused by the death and dysfunction of these neurons in the brain.

Treatment with the STARs increased GCase protein levels and transport to lysosomes, and raise levels of GCase enzymatic activity, results showed.

Dopaminergic neurons treated with GT-02287 and GT-02329 also had lower levels of the phosphorylated alpha-synuclein protein, indicating they might treat GBA1-associated Parkinson’s disease.

“The topline data demonstrates that our STARs compounds open a new potential approach for direct treatment of GBA1 Parkinson’s Disease by guiding misfolded forms of the GCase enzyme to their proper shape and restoring enzymatic activity,” said Manolo Bellotto, PhD, general manager at Gain Therapeutics.

“These encouraging results show promise for this approach to correct dysfunction in the GBA1 pathway, a leading target for Parkinson’s drug development,” said Marco Baptista, PhD, vice president of research programs at the Michael J. Fox Foundation, which supported work leading to these studies.

“We look forward to hearing more on next steps to advance these potential therapies further in testing and closer to patients whose greatest unmet need is a treatment to slow or stop disease progression,” Baptista added.

As small molecules, STARs can be administered to patients as an oral pill, Gain reported, which could be an advantage over current therapies as they might reach organs and tissues not typically accessible with existing treatments. The company also expects that STARs will be relatively easy and cost-effective to manufacture.