MJFF grant to fund preclinical study of paxalisib for Parkinson’s
Kazia seeking to advance anticancer drug as potential Parkinson's treatment
A grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) will allow Australia-based Kazia Therapeutics to explore the potential of paxalisib — an investigational anticancer drug now being tested in clinical trials — as a repurposed treatment for Parkinson’s disease.
The research grant will fund collaborative preclinical studies at The Hebrew University of Jerusalem, in the lab of Ronit Sharon, PhD. This work will explore the link between a pathway involved in Parkinson’s disease, called phosphatidylinositol 3-kinase, or PI3K, and paxalisib, a PI3K inhibitor.
Data from this project is expected to provide evidence of the potential use of paxalisib as a treatment for Parkinson’s, according to the new research partners.
“We are pleased to enter into this exciting collaboration with Dr. Ronit Sharon and The Hebrew University of Jerusalem, whose groundbreaking research has led to important discoveries related to neuronal [nerve cell] degeneration in Parkinson’s disease,” John Friend, MD, Kazia’s CEO, said in a press release.
Paxalisib found to stop activation in mice of pathway key in Parkinson’s
Parkinson’s is caused by the dysfunction and loss of dopaminergic neurons, the nerve cells that produce dopamine, which is a brain signaling molecule involved in motor control. A hallmark disease feature is the formation of toxic clumps, mainly composed of misfolded alpha-synuclein, thought to drive nerve cell dysfunction.
Ronit, an assistant professor at the university, has focused her work on the function of alpha-synuclein in both the healthy brain and ones affected by Parkinson’s.
Previous findings from Ronit’s lab, obtained from patient brains and a mouse model of the disease, have shown the PI3K pathway plays a role in Parkinson’s development. Particularly, alpha-synuclein appears to hyperactivate this pathway.
Paxalisib is an experimental anticancer medication designed to stop the activation of the PI3K pathway that’s also overactive in some brain cancers. The drug candidate can enter the brain, and its efficacy in treating brain cancers is now being assessed in clinical trials.
We believe paxalisib may have the potential to address the underlying pathophysiology [functional changes linked to the disease] of [Parkinson’s]. … The preclinical models we intend to explore will help answer this critical question.
Due to its ability to penetrate the brain and inhibit the PI3K pathway, the researchers hypothesized that paxalisib may be repurposed as a treatment for Parkinson’s. Â Their studies will use a Parkinson’s mouse model that expresses a mutated form of the human alpha-synuclein, called A53T. The animals will be given paxalisib orally at a dose of 20mg/kg/day, for 28 days, or nearly one month. Animals without the mutation will be used as controls.
The team will analyze paxalisib’s effect on disease biomarkers related to alpha-synuclein in the brain and cerebrospinal fluid — the fluid that surrounds the brain and spinal cord — through biochemical and gene expression analysis, and cellular hallmarks of the disease. The researchers also will assess the treatment’s effects on mouse survival, as well as motor and nonmotor abilities.
“As a brain-penetrant PI3K inhibitor, we believe paxalisib may have the potential to address the underlying pathophysiology [functional changes linked to the disease] of [Parkinson’s] by inhibiting AKT phosphorylation reaction of [alpha]-SynA53T,” Friend said. “The preclinical models we intend to explore will help answer this critical question.”
Paxalisib was originally developed by Genentech, which has entered a worldwide exclusive license agreement with Kazia.
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