Promising Parkinson's Disease Treatment Candidate Identified in Mouse Study

A new study has identified a promising drug candidate that can protect neurons from degeneration in mouse models of Parkinson’s disease. The research is published in Science Translational Medicine.

Addressing an unmet need

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and over the last 25 years, the prevalence of PD has doubled, presenting a large health burden across the globe.

PD is characterized by motor problems i.e., problems with movement. These include slow movement, tremors and impaired balance – in some cases, PD can also cause cognitive problems including impaired memory and attention.

Previous studies have linked the development of PD to errors in a protein called alpha-synuclein (α-synuclein). When α-synuclein proteins fail to fold properly, they can be taken up into the affected neurons and activate an enzyme called cellular Abelson tyrosine kinase (c-Abl). Activation of c-Abl phosphorylates α-synuclein, which may in turn promote the progression of PD. Interestingly, other studies in models of α-synuclein-dependent PD have shown that inhibiting c-Abl may be a promising avenue to halt the progression of the disease.

Some existing drugs, such as levodopa and carbidopa, can help to manage the symptoms of PD, but there are currently no established therapies that can prevent or slow its progression.

In the current study, the researchers applied their own drug discovery strategy to design and test potential inhibitors for c-Abl, with the aim to develop new therapies that may limit the progression of PD.

RAMPing up drug discovery

The researchers used a method called “re-engineering approach with metabolism preserved” – or RAMP – to assess a library of potential c-Abl inhibitors. Their aim was to identify compounds that would more selectively inhibit proteins c-Abl1 and c-Abl2, and not other members of the c-Abl family of proteins.

Dr. Milton Werner, one of the lead authors of the study and CEO of Inhibikase Therapeutics, explained this approach further: “RAMP uses existing pharmacological and chemical data to learn from an existing molecule and impart new properties based on rational structure–design principles. Source data for this approach treats a related molecule as a template for further modification in order to build in new features to give rise to candidates with improved pharmacological properties relative to the template.”

Promising molecules identified by RAMP were then evaluated in a mouse model to determine how much of the compound reached the brain and how effective it was at suppressing c-Abl. Based on their criteria, the researchers selected a compound named IkT-148009, which was well absorbed into the bloodstream when taken by mouth and was able to pass through the blood–brain barrier.

IkT-148009 also suppressed c-Abl activation and protected neurons from additional degeneration when given daily to mouse models of progressive, α-synuclein-dependent PD. Movement and motor function also improved in the mice within 8 weeks of starting treatment, alongside a reduction in the buildup of α-synuclein in the brain.

“We believe this validates IkT-148009 as a possible disease-modifying treatment of PD and alters the treatment paradigm for the disease,” Werner adds.

Next steps and clinical trials

Werner explains that the drug candidate is currently being evaluated in early Phase 2 trials in untreated PD patients. “We hope to learn that the drug is impacting various aspects of Parkinson’s disease following several months of daily treatment. We are also exploring the safety and tolerability of the drug in the treatment population. If successful, these studies will be expanded to longer-term treatment studies to evaluate efficacy in multiple treatment populations,” Werner concludes.

Reference: Karuppagounder S, Wang H, Kelly T, et al. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson’s disease. Sci. Transl. Med. 2023;0(0). doi: 10.1126/scitranslmed.abp9352

Dr. Milton Werner was speaking to Sarah Whelan, Science Writer for Technology Networks.