Parkinson’s preclinical research on dapansutrile awarded grant

Funding to go toward potential therapy to prevent, lessen Parkinson's symptoms

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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Olatec Therapeutics has been awarded a grant from the Michael J. Fox Foundation for Parkinson’s Research (MJFF) to further investigate its lead oral candidate, dapansutrile, in animal models of Parkinson’s disease.

Such preclinical work will be conducted in collaboration with researchers at the Medical University of Innsbruck in Austria to accelerate the development of this potential therapy to prevent or lessen the development of the disease’s symptoms.

Under this grant, of which the amount was not specified, the team will evaluate dapansutrile’s potential as an anti-neuroinflammatory therapy in specific Parkinson’s mouse models.

“We are very pleased to receive this grant from the MJFF and are hopeful the findings will advance us into a clinical trial with dapansutrile in Parkinson’s disease,” Charles Dinarello, MD, Olatec’s scientific advisory board chairman and chief scientific officer, said in a company press release.

“I am also thrilled to launch our collaboration with Olatec and the lab of Charles Dinarello with the funding support of MJFF, and to work on the preclinical evaluation of dapansutrile for the treatment of PD [Parkinson’s disease] and related disorders,” said Nadia Stefanova, MD, PhD, the study’s lead investigator and a professor in the department of neurology at the Medical University of Innsbruck.

Stefanova is an expert on alpha-synucleinopathies, a group of diseases, such as Parkinson’s, that are marked by the buildup of toxic clumps of the alpha-synuclein protein in the brain.

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Slowing formation of protein clumps

In Parkinson’s, these toxic aggregates contribute to the progressive death of dopamine-producing neurons in a part of the brain called substantia nigra. The resulting dopamine deficiency in the brain can cause not only the disease’s hallmark motor symptoms, but also nonmotor symptoms such as cognitive impairment.

There are currently no therapies that can alter Parkinson’s progression. Standard treatments like levodopa can reduce symptom burden but are unable to modify disease progression.

Alpha-synuclein accumulation may start or run parallel to an inflammatory cascade resulting in neuron loss. Thus, tuning down neuroinflammation processes may prevent or slow the formation of the protein clumps.

Dapansutrile, also known as OLT1177, is an orally available small molecule designed to specifically bind to and block NLRP3, a protein that normally patrols the inside of cells to detect danger signals.

When NLRP3 detects a threat, it can trigger the formation of an inflammasome, a multiprotein complex that promotes the release of proinflammatory signaling molecules, such as IL-1beta and IL-18, and an inflammatory form of cell death.

By targeting NLRP3, dapansutrile prevents the formation of the NLRP3 inflammasome, thereby reducing the production of IL-1beta and IL-18.

The experimental therapy has been generally well tolerated and associated with positive clinical outcomes in prior clinical trials involving people with other NLRP3 inflammasome-mediated conditions.

Previous work in a standard mouse model of Parkinson’s showed dapansutrile reduced IL-1beta and IL-18 levels in the brain, resulting “in [significantly] improved locomotion and lower brain levels of the [toxic alpha-synuclein],” Dinarello said.

The upcoming studies will test the therapy in two other mouse models of Parkinson’s: one genetically modified to produce human alpha-synuclein and the other injected with preformed toxic alpha-synuclein clumps.

The team will evaluate whether dapansutrile can reduce neuroinflammation and alpha-synuclein clumps, protect dopamine-producing neurons from death, and prevent motor deficits in these models.

The therapy’s tolerability and pharmacokinetics, the movement into, through, and out of the body, also will be assessed.

“A Phase 2 clinical trial in people with PD and related alpha-synucleinopathies could start as soon as practical following successful completion of the proposed preclinical studies,” the researchers wrote in the description of their awarded project.

“Olatec is very pleased to be awarded this grant, and to be collaborating with Dr. Stefanova on this important research evaluating dapansutrile in the potential treatment of this debilitating disease with unmet medical need,” said Damaris Skouras, Olatec’s founder and CEO.