# Advanced therapeutic for Parkinson's Disease

> **NIH NIH R44** · INHIBIKASE THERAPEUTICS · 2020 · $1,546,730

## Abstract

Parkinson's Disease (PD) is a progressive neurodegenerative disorder that affects ≈1 million patient in the U.S.
annually and 7 to 10 million people worldwide. PD is characterized by disorders of movement, which are
caused by the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc), and
autonomic dysfunction, anxiety, depression, sleep disorders and cognitive impairment that are due to the
degeneration and dysfunction of other neuronal populations. To date there are no pharmaceutical therapies
that impede or prevent the neurodegeneration characteristic of the disease. Although dopamine replacement
therapy alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses,
leading to unacceptable side effects, such as severe motor fluctuations and dyskinesias. Moreover, this
palliative therapeutic approach does not address the underlying mechanism(s) of the disease. Although the
etiology of PD is not yet entirely clear, there is an abundance of data indicating that increased oxidative stress
in dopaminergic neurons of the SNpc significantly contributes to the pathogenesis of PD. c-Abl tyrosine kinase
has been revealed as a key checkpoint in the brain and c-Abl phosphorylation (i.e. activation) is robustly
increased in PD brain, in animal models of a-synucleinopathies and also in the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP)-induced preclinical animal model of PD. Activated c-Abl can phosphorylate
parkin, leading to inhibition of parkin's E3 ligase function and accumulation of its toxic substrates, PARIS
(PARkin Interacting Substrate) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2
(AIMP2). c-Abl1/2 inhibitors restore parkin's E3 ligase activity, reduce the accumulation of parkin substrates,
and protects against MPTP-induced neurotoxicity in vitro or in vivo. Activated c-Abl also phosphorylates a-
synuclein, driving both a-synuclein aggregation and production of toxic aggregates that are responsible for
neurodegeneration. Taken together these results suggest that inhibition of c-Abl activation could be an
effective disease modifying therapy for PD. The present proposal will complete the pre-clinical toxicology
requirements for chronic drug administration to Parkinson's patients while the lead drug, IkT-148009, is
completing initial healthy volunteer studies.

## Key facts

- **NIH application ID:** 10020202
- **Project number:** 5R44NS103695-04
- **Recipient organization:** INHIBIKASE THERAPEUTICS
- **Principal Investigator:** Milton H. Werner
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,546,730
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020202

## Citation

> US National Institutes of Health, RePORTER application 10020202, Advanced therapeutic for Parkinson's Disease (5R44NS103695-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10020202. Licensed CC0.

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