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.
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.
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 – 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 is being clinically tested in the Sun Pharma SPARC large Phase II “PROSEEK” study, which involves 500+ participants.Find out more
FB-101 is being clinically tested by 1ST BiotherapeuticsFind out more
IkT – 148009
Biotech company Inhibikase is testing its molecule – IkT-148009Find out more
These novel drugs have been designed to achieve better brain penetrance. The trials will include more appropriate measurement of target engagement, such as highly sensitive imaging tools, for testing whether c-Abl inhibitors do have a disease modifying effect in Parkinson’s and therefore potential to slow, stop or even reverse Parkinson’s.
C-Abl remains of great interest to Cure Parkinson’s.
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