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!

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