Innovation Partnership

­­­­From Discoveries to Treatments

The rate of discovery of promising potential new drugs and therapeutic approaches has recently increased in university labs, fueled by advances in both research technology and genomic medicine. However, the gap between the lab and the market—the "valley of death"—continues to widen as both government and investor funding of biomedicine decline. Steve Weiss and Alan Saltiel have developed new therapeutics with support from the Innovation Partnership.

Conceived of and designed by LSI’s Leadership Council, the Innovation Partnership takes on this challenge by infusing the projects of LSI scientists with funding and expertise from leaders in the top ranks of business, venture capital, and the biomedical industry. With $1.2 million raised from donors, the Innovation Partnership has funded four faculty projects, all of which have achieved critical commercialization milestones with mentorship from the ranks of the council.  Fundraising continues and new faculty projects are in the pipeline.

"The partnership enables a seamless transition from research into development," David Walt, member of the LSI Leadership Council and co-founder of Illumina, Inc. and Quanterix Corp.

Developing a new drug to treat Type 2 diabetes

Investigator:  Alan Saltiel, PhD, former Mary Sue Coleman Director of the Life Sciences Institute and Professor of Internal Medicine and Molecular and Integrative Physiology. Alan Saltiel and a lab member in the LSI

Disease problem: Tens of millions of Americans have been diagnosed with Type 2 diabetes and millions more remain undiagnosed. Most patients with type 2 diabetes are obese, and Saltiel and his lab explore how the conditions are linked. They honed in on an interesting new hypothesis: The link is inflammation caused by obesity, and that inflammation causes Type 2 diabetes. Saltiel’s lab identified a gene, IKKE, which appears to act in the inflammation pathway to moderate energy expenditure and its downstream effects like weight and sensitivity to insulin.

Partnership: Through screening of tens of thousands of chemical compounds in LSI’s Center for Chemical Genomics, the scientists discovered that an off-patent drug, amlexanox, blocked the activity of IKKE. Follow-up studies revealed that amlexanox caused diet-induced and genetically obese mice to lose weight and prevented problems like diabetes and fatty liver disease. This breakthrough was published in Nature Medicine. The Innovation Partnership is funding follow-up studies on modifying the compound for testing in human trials.     

Outcome: A small clinical trial in humans is underway. U-M has filed a patent on the use of amlexanox for treating metabolic disease and on related chemical compounds. Follow-on funding is being sought from government and private investors.

 

Creating novel anti-metastatic drugs for treating cancer

Investigator: Stephen J. Weiss, MD, Professor of Internal Medicine

Disease problem: The vast majority of cancer deaths are due to metastasis, yet the mechanisms underlying this process remain poorly understood. The Weiss lab has been interested in understanding how and why cancer cells move through tissues to distant sites.

Partnership: Building on a novel 3-D research platform and a data-driven experimental approach conceived by Weiss, the partnership funded studies to find monoclonal antibodies to metastasis of breast, pancreatic and glioblastoma cancer cells. The approach has yielded more than 50 potential leads for promising antibodies. With the advice and guidance of the LSI’s Leadership Council, a handful of these have been further investigated showing efficacy in halting metastasis in animal models.  

Outcome: University of Michigan has filed for patents on three of the most promising lead antibodies. The research platform continues to produce exciting possibilities across several types of cancer as well as yield insights into the underlying biology of metastasis. Follow-on funding is being sought from investors and business alliances are being explored.

 “This is a perfect example of an approach that would not be suitable for traditional funding—it’s a great idea but just needed the experimental traction that could only be obtained through innovative funding.”—David Dudley, LSI associate research scientist in the Weiss lab

 

Focusing on a key pathway that controls the virulence of strep and other infections

Investigator: David Ginsburg, MD, Howard Hughes Medical Institute Investigator and Professor of Internal Medicine and Human Genetics.

Disease Problem: There are several million cases of strep throat and more than 10,000 cases of invasive group A Strep (GAS) diseases in the U.S. each year. Some are fatal. Interested in the relationship between the blood-clotting system and how we protect ourselves from bacterial infections, LSI faculty member David Ginsburg and his lab discovered that the human body uses blood clots to surround the Strep A bacterial infection as a natural defense. However, the Strep A bugs make a protein called  streptokinase that activates human plasminogen and dissolves the blood clots, allowing the infection to spread rapidly throughout the body. This observation led the Ginsburg team to wonder whether they could render the bacteria innocuous by blocking production of streptokinase and in the process also reduce the threat of antibiotic resistance.

David Ginsburg and a lab member in the LSIPartnership: The lab, along with collaborators at the U-M Vahlteich Medicinal Chemistry Core and at the University of Missouri, searched for small molecules that turned off the production of the protein in live bacteria, with the hope that they could interfere with the mechanism used by the bacteria to spread the infection.  After screening tens of thousands of chemicals in the LSI’s Center for Chemical Genomics and other facilities, the team identified many promising lead compounds and refined two of them for further exploration.

Outcome: University of Michigan filed patents on the two leading compounds. The chemical screening also helped the team refine its hypothesis about the biological target being exploited by the bacteria; this discovery was published in the Proceedings on the National Academy of Sciences. Armed with this knowledge, the team is applying for new government research funds to further explore the target and accelerate the drug discovery efforts.

“We wouldn’t have pursued the project to the stage that we’re at now without the funding and advice provided by the Innovation Partnership.” —David Ginsburg

Targeting the protein quality control pathway yields results in treating Alzheimer’s and other diseases

Investigator: Jason Gestwicki, PhD, now Associate Professor of Pharmaceutical Chemistry at University of California, San Francisco

Disease Problem: About 5.3 million people have Alzheimer’s disease, which is caused by abnormal protein misfolding and accumulation that leads to the formation of a neurotoxic tangled structure in the brain that kills neurons for good. Former LSI faculty member Jason Gestwicki was interested in this question: What prevents this from happening in everyone?

Partnership: The team searched for small molecules that stimulate the activity of a protein called Hsp70, which prevents the protein misfolding in brain cells that causes progressive neurological diseases like Alzheimer’s. After screening tens of thousands of potential compounds in the LSI’s Center for Chemical Genomics, the Gestwicki team identified two particularly interesting chemicals and figured out how they bind to and regulate Hsp70.

Outcome: The university filed composition of matter patents on the two chemical leads. In addition, Gestwicki entered into agreements with two companies, Proteostasis Therapeutics, Inc. and Abbott Laboratories, to screen an additional 65,000 compounds. An additional $750,000 in external funding from multiple sources was secured to continue the drug discovery process.