Inhibiting "KMO" enzyme protects against neurodegeneration
Candidates—Daniel Zwilling and Lily Huang, UCSF
Nominated by Paul Muchowski, UCSF
Daniel Zwilling and Lily Huang with Prof. Paul Muchowski (right).
The Deloitte QB3 Award for Innovation recognizes a graduate student, postdoc, staff scientist, or team from UC Berkeley, UC Santa Cruz, or UCSF who has made an advance with the capacity to improve human health. Candidates for were nominated by QB3 faculty. Finalists were chosen by a panel of expert judges.
We asked each nominee (or team) to answer a series of short questions, to give a snapshot of their project. Read their answers below. Leave a comment to let us know what you think!
Please describe your innovation.
We demonstrated that a metabolic pathway of tryptophan degradation (kynurenine pathway, KP) has a critical role in Alzheimer’s and Huntington’s diseases. First, while the pathway had long been suspected in neurodegeneration, the novel small molecules we created allowed us to test this hypothesis for the first time. Second, our drug (JM6) does not enter the brain and acts solely in the blood. Inhibiting a key KP enzyme (kynurenine 3-monooxygenase) in the blood ameliorates brain pathology and behavioral symptoms in mouse models of Alzheimer’s and Huntington’s diseases by sending a neuroprotective signal to the brain.
The KMO inhibitor JM6 increases brain levels of kynurenic acid by blocking the enzyme in blood cells. This relieves symptoms in mouse models of Huntington’s and Alzheimer’s diseases.
How does your research topic represent a strong advance in human health? And how will it influence the way we operate in science in the future?
Millions of people are suffering and eventually dying from these diseases for which no cures exist. Using our orally available drug in mouse models of Alzheimer’s and Huntington’s diseases, we identified a novel mechanism of neurodegeneration and showed that excitotoxicity and subsequent neurodegeneration can be prevented by inhibiting an enzyme (kynurenine 3-monooxygenase) in the blood. Safety and toxicology studies are being performed in anticipation of an impending safety trial in humans. Hopefully, our therapeutic strategy will result in novel drugs for neurodegenerative disease and eventually help patients suffering from Alzheimer’s and Huntington’s diseases and possibly other neurodegenerative diseases.
Within the 140-character Twitter limit:
What’s the impact?
We found a potential new treatment for neurodegeneration. It could affect the currently 5M Alzheimer’s disease and 30,000 Huntington’s disease patients
What’s the novelty?
No cure exists for Alzheimer’s or Huntington’s disease. Our drug works in blood but treats neurodegeneration in the brain. Tests in human patients planned for 2013
What’s the utility?
Kynurenine biology is well characterized. We elucidated the drug mechanism in behavioral, neuropathological, and biochemical studies. Clinical trial coming up!
Reference:
Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration
Daniel Zwilling, Shao-Yi Huang, et al.
Cell, Volume 145, Issue 6, 10 June 2011, Pages 863-874
Comments
Ron (not verified)
September 25, 2011 - 3:59pm
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Fascinating work
What exciting work! Since glutamate receptor-mediated excitotoxicity is a common theme in a lot of brain diseasese and injury, might this provide even broader applications than just AD and HD - not that those aren't major unmet needs?
Daniel Zwilling (not verified)
September 28, 2011 - 9:20am
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Applications for new drug
Hi Ron,
Thank you for your comment! You are right. While we concentrated on AD and HD it is well known that glutamate mediated excititoxicity may really be the underlying mechanism for many other neurodgenerative diseases. We hope that our findings will trigger more research in other labs that will now explore KMO and the kynurenine pathway as new potential targets.
Dan (not verified)
October 24, 2011 - 10:32am
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Comment about our work on F1000
This is a comment about our work on Faculty 1000:
http://f1000.com/13327977
Dan (not verified)
October 24, 2011 - 10:38am
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Review on our work and the kynurenine pathway in disease
Another article about our work in Nature Reviews drug discovery:
http://www.nature.com/nrd/journal/v10/n8/full/nrd3521.html
Deborah Kallick, PhD (not verified)
November 28, 2011 - 11:17am
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quesiton about discovery
Hello,
what a great discovery. I look forward to reading the detials about this work. Where will yhou publish?
Do you have your lead compound? Have you done any formulatin work for your mouse models? Are you trying to mimice what would be your 'active pharmaceutical ingredient' by perparing formulated compound?
I'm a consultnat in preclinical development and perhaps we can talk one day. I plan to attend QB3 events more regularly.
Kind regards,
Deborah Kallick, PhD
Infinity Resaerch and Consulting, Ltd
650-852-0853
Deborah Kallick, PhD (not verified)
November 28, 2011 - 11:19am
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Hello,
Hello,
i posted without spell checking, my apologies!
Deborah
Dan (not verified)
December 6, 2011 - 11:16am
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Dear Deborah,
Dear Deborah,
Thank you so much for your comment.
We published this in Cell in June. http://www.ncbi.nlm.nih.gov/pubmed/21640374
The JM6 is actually a pro-drug for the KMO inhibitor Ro 61-8040. The drug was added to the food and is digested in the guts and released into the blood.
Please let me know if you have any other questions.
Sincerely,
Dan
Anna Gardner (not verified)
July 27, 2012 - 10:43pm
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Hi,
Hi,
We have Huntington's disease in our family and it has been devastating. Will this drug be available for human testing in all parts of the world in 2013? My mother who has this disease lives in New Zealand.
kaspar mossman
August 20, 2012 - 3:34pm
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Dan asked me to post this
Dan asked me to post this response (since he had trouble leaving a comment):
Dear Anna,
I’m sorry to hear about your family and I can only imagine how difficult this must be. The drug is now in preliminary testing phases for clinical drug trials. These clinical trials have to be completed and the results need to be evaluated first, before going to the next steps. At this point nobody can say when this drug may be available to patients.
Please check with the HD society (http://www.hdsa.org/) for news and information on HD drug trials and you can also check the Gladstone Institutes web page for news on our specific drug (http://gladstoneinstitutes.org/).
I hope that there will be a treatment for HD available soon, and I can assure you that researchers around the world are working very hard on finding one.
I wish you and your family all the best!
Dan
zorgan kosovich (not verified)
January 15, 2013 - 9:16pm
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I wish your family the best.
I wish your family the best. Remember, much of this research is high-stakes and it needs to be repeated by other laboratories. If there are few side-effects and the doses are sufficiently low, one might consider trying it, but please be careful. The drug is not chemically very complex and is easy to synthesize, with large-scale routes available in the literature. In principle a medicinal chemist at a university could make this compound in large quantities for the cost of 1 weeks work plus <$1000 in materials. I do not advocate this as it could be very dangerous and you should consult with a physician before even thinking of consuming these drugs on your own. That being said, my point stands that the molecule itself is not very complicated.
One more thing: The lead author of this study Paul Muchowski has recently been convicted of falsifying data and has been fired from his institution and barred from doing NIH supported research without supervision.
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