Potential Parkinson’s Treatment Focuses on Protecting Mitochondria

Early studies show 2 molecules aid cell energy sources but not alpha-synuclein

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An image of mitochondria, a component of cells that supply the cell's with energy and are essential to cellular health.

Two small molecules in the pipeline of Lucy Therapeutics helped nerve cells (neurons) keep their mitochondria healthier and reduced the levels of  alpha-synuclein, a protein that builds as toxic clumps in the brain of people with Parkinson’s disease.

These molecules, called LucyTx-1209 and LucyTx-1212, also were seen to be safe when tested in cell and rodent models of the disease. The company is working to select the best candidate to potentially bring into clinical testing.

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Mitochondria are the cell’s powerhouses and problems in the workings of these small organelles have been implicated in neurological diseases such as Parkinson’s and Rett syndrome. Restoring mitochondrial function could provide a way to normalize neuronal health in people with these diseases.

“Lucy Therapeutics wants to create a world in which mitochondrial-involved neurological diseases like Parkinson’s or Rett syndrome can be halted when diagnosed,” Amy Ripka, PhD, Lucy’s founder and CEO, said in a press release.

Protecting mitochondria by blocking an enzyme complex tied to Parkinson’s

To work as they should, mitochondria rely on the activity of many enzyme, or protein, complexes. When some of these complexes shut down or go awry, problems in cells can arise.

Changes in F1F0-ATPase, an enzyme complex that helps speed the production of the energy-storing molecule ATP, are associated with Parkinson’s. LucyTx-1209 and LucyTx-1212 were designed to block F1F0-ATPase with high selectivity and potency.

“The high selectivity and potency of two of our lead small molecule agents, LucyTx-1209 and LucyTx-1212, in inhibiting a target we believe is at the nexus of several mitochondrial pathways contributing directly to Parkinson’s disease represents a significant advance for our mission to develop first-in-class therapies for neurological diseases,” said Roland Staal, PhD, director of pharmacology at Lucy.

In preclinical studies, company researchers observed that inhibiting F1F0-ATPase with either LucyTx-1209 or LucyTx-1212 led to better mitochondrial health in neurons. The small molecules also helped to lower the levels of alpha-synuclein, the protein whose accumulation leads to the death of neurons in Parkinson’s disease.

Staal presented these findings in an oral presentation at this year’s Parkinson’s Disease Therapeutics Conference, sponsored by the Michael J. Fox Foundation and held Oct. 13 in New York City.

“We have demonstrated that our compounds can rescue neurons in cellular models of Parkinson’s disease, validating our therapeutic approach. We did not observe any significant safety issues with the use of LucyTx-1209 or LucyTx-1212 in pre-clinical laboratory or rodent studies, so we will now focus on studies to select the best candidate to advance for clinical trials,” Staal said.

Earlier this year, the company received a two-year, $4.9 million grant from the foundation to advance work in a number of mitochondria-targeting compounds that could lead to new Parkinson’s treatments.

“The grant and support from the Michael J. Fox Foundation has helped our scientists significantly speed our investigations,” said Ripka, adding that the company’s small molecules “have great potential for further development.”