Drug Rescue of PINK1 Kinase Activity - A New Therapeutic Modality For Treating PD
Rapid Response Innovation Awards, 2011
This grant builds upon the research from a prior grant:
Many genetic disorders are caused by the loss of a functional protein which protects cells from disease. These disorders are difficult to treat with drugs because most drugs block the function of a particular protein. This project seeks to rescue the activity of a mutant protein important in Parkinsonís disease. We have made a surprising discovery that the enzyme PINK1 in its Parkinsonís mutant form can be made active if we provide it with a designed non-natural substrate drug.
We now have solid biochemical evidence that our drug candidate can increase the function of the PINK1 kinase, which is important for neuronal survival in response to stress. We are now progressing to the critical stage of testing our drug candidate in human cells of both non-neuronal and neuronal types. We will be using microscopy and fluorescent proteins to visualize processes in the cells which are thought to be dependent upon PINK1 activity. Our experiments will be designed to test the structural requirements of our drug candidate for efficacy in neuronal protection. We will work to make a solid link between our drug candidate and the PINK1 enzymeóand show that by adding our rescue drug to neurons we can protect them from death in a PINK1 dependent manner.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
This project is very ambitious and risky, since there are no real precedents for treating this kind of genetic disorder with a drug. However if we are successful, I think it will open the door to a new therapy for Parkinsonís patients. A chemical which can rescue an inactive enzyme required for neuronal survival would be a very exciting medical advance. The ability to genotype patients and provide them a custom drug regimen would be particularly helpful because it would allow only the patients with a strong likelihood of benefiting from the drug to be given the drug. I want to stress again that this is a very risky approach but we are excited about the opportunity to explore it vigorously.
We hope to provide robust and comprehensive cellular data on a new potential drug to treat Parkinsonís disease. The strategy we are taking is risky and really unprecedented but we have solid evidence in simplified systems that we can increase the function of a neuroprotective kinase, PINK1, strongly implicated in Parkinsonís disease. If the proposed work is successful, we will be in a position to test our molecules in pre-clinical models.
INTERIM PROGRESS REPORT
Our research has identified a small drug molecule which activates an enzyme (PINK1) involved in protecting neurons from stress. †This enzyme is mutated and inactivated in patients with early onset PD. †The identification of a drug which can selectively activate this enzyme is very exciting as it could provide a disease modifying therapy rather than a therapy designed to treat the symptoms. †The other feature of this drug which makes it appealing is that it is approved for human testing already which may accelerate future clinical trials.
Presentations & Publications
Abstract and Poster at Chemistry and Biology Keystone Meeting in February 12th-16th, 2012. The meeting can be found on this site (http://bit.ly/UhRpmD).
Howard Hughes Medical Institute Investigator and Professor at University of California, San Francisco
Chair of the Scientific Advisory Committee at Mitokinin LLC
Location: San Francisco, California, United States