A protein called Abelson Tyrosine Kinase – or c-Abl – is believed to be involved in the biological processes leading to loss of dopamine neurons in the brains of people with Parkinson’s.
In many preclinical studies, stopping the harmful c-Abl processes with the use of drugs called c-Abl inhibitors have found that c-Abl activity decreases. There is also evidence that the toxic protein alpha-synuclein is reduced.
The association between c-Abl activation and alpha-synuclein accumulation has been demonstrated in samples of brain tissue. Alpha-synuclein accumulation is a characteristic of Parkinson’s and its presence causes an inflammatory stress in cells.
Research therefore suggests preventing c-Abl activation may be a promising disease-modifying therapy.
In 2010, Professor Ted Dawson (a member of Cure Parkinson’s International Linked Clinical Trials committee) and his research team at Johns Hopkins University School of Medicine reported that c-Abl is activated in the brains of people with Parkinson’s. They also found that inhibiting this protein had a neuroprotective effect in models of Parkinson’s. This study has been independently replicated by multiple research groups, indicating that c-Abl is a potentially important target for research into slowing the progression of Parkinson’s.
There is a strong scientific rationale to study c-Abl inhibitors in Parkinson’s disease, since multiple studies have shown the c-Abl inhibition is protective in multiple models of Parkinson’s disease.
Professor Ted Dawson
Clinical Evaluation
Subsequent to this preclinical research, a very small pilot clinical study was initiated in people with Parkinson’s using a c-Abl inhibitor drug called Nilotinib – a clinically available drug already used in the treatment of leukaemia. Initial safety tests in people with Parkinson’s, and a larger, placebo controlled clinical trial, supported by Cure Parkinson’s and the Michael J Fox Foundation, to assess Nilotinib in a blinded approach, showed limited effect due to poor brain penetrance.
The Progress of Novel c-Abl inhibitors
There are further novel c-Abl inhibitors now being clinically tested which demonstrate a more effective penetrance and target engagement. These trials include:
K0706
K0706 is being clinically tested in the Sun Pharma SPARC large Phase II “PROSEEK” study, which involves 500+ participants.
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