By Cynthia Robbins-Roth

BioWorld Today Columnist

Thirty-four years ago, the trustees of the J. David Gladstone Foundation and their scientific advisors decided to use the bulk of the entrepreneurial real estate pioneer's $8 million estate to create an independent medical research institute.

The Gladstone Laboratories opened in 1979 with a mandate to conduct basic research for translation into new treatments for cardiovascular disease - the leading cause of death in the U.S. Its partnership with the University of California- San Francisco and San Francisco General Hospital provided access to the clinical world.

The initial focus was driven by Director Robert Mahley, who left his post as head of the Comparative Atherosclerosis and Arterial Wall Metabolism Section at the National Heart, Lung & Blood Institute at the National Institutes of Health, of Bethesda, Md., and brought his research team along.

Mahley and his group were deciphering the drivers of atherosclerosis and did much of the early work on the role of lipoproteins, including ApoE, which carry fat through the blood.

Today, that endowment is $200 million and has provided more than $200 million in research support. Mahley now is president of Gladstone, with more than 340 staff, an annual budget exceeding $50 million (research grants and the endowment) and 39 issued patents.

The original cardiovascular institute has a new director, Deepak Srivastava, and the research has expanded to include targets for atherosclerosis drug design, cardiac stem cells, enzymes controlling fat synthesis and storage and their roles in disease, understanding genetic risk factors, gene mutations in valve disease and cardiac muscle maintenance, and further understanding the structure and role of ApoE.

In 1992, the Gladstone Institute of Virology and Immunology was formed to aim basic research at the growing HIV pandemic. San Francisco General Hospital was ground zero for much of the early patient care in the 1980s. The institute was second only to NIH in funding basic research for HIV/AIDS.

Under Director Warner Greene, the GIVI scientists work on HIV prophylaxis and improved treatment, HIV latency - which prevents cures, deciphering just how the virus leads to die-off of crucial immune and blood cells, and mechanisms of viral gene control.

Segue into the brain

GIVI's studies of NF-kB, a key protein in inflammatory and immune responses, found that this same regulatory protein is crucial in learning and memory through its control of proteins required for long-lasting neuronal connections.

This serendipitous discovery is being explored in conjunction with the newest member of the family, the Gladstone Institute of Neurological Disease. The GIND was created in 1998 based on the unexpected discovery by the original Gladstone team that ApoE also plays a role in the response of the brain and peripheral nervous system to injury.

The discovery was extended when Alan Roses and his group at Duke University found a correlation between the E4 variant of ApoE and increased risk for Alzheimer's disease. E4 is the strongest genetic factor tied to the risk of Alzheimer's, with 40 percent to 60 percent of those patients carrying that gene.

Lennart Mucke became director of the new institute. The team has a Neurobehavioral Core Lab developing quantitative methods for assessing response to treatment, and is exploring the 3-D structure of the misfolded protein causing Huntington's disease, the role of specific brain cell types in diseases, novel targets for drug design and understanding how amyloid buildup in the brain causes symptoms.

Translation into products

As the science has blossomed, Mahley has become more concerned about that translational process discussed frequently in this column. Ever since the Gladstone moved in 2004 to the UC-SF Mission Bay campus - dedicated to the concept of translational research - he has watched the funding gap grow as venture funds and the federal government reduced their support of preclinical research.

Mahley realized that Gladstone needed to find a way to boost its science to a point where corporate partners and investors would shoulder the financial and development burden. He also realized that simply spinning the technology off into start-up companies was not the answer. It might be possible to get that first $500,000, but many important inventions have vanished because the start-up starved before reaching clinical validation.

Leading off with his strongest asset, the ApoE/Alzheimer's program, Mahley and his advisors came up with the idea for the Gladstone Center for Translational Research. In the fall, Merck stepped up with a deal that includes an up-front fee of $3.25 million, at least four years of research support, the usual milestones and royalties in case of success.

Mahley is putting the center in the building next door, which also houses Sirna Therapeutics - Merck's latest acquisition. The team, encompassing the scientists from the Institute program (but no students or post-docs), will be looking for drug candidates aimed at three novel targets related to ApoE4 and its attack on neurons. The center team will be able to access Gladstone's resources while maintaining separate intellectual property and making accounting easier.

Stephen Freedman, former head of R&D at Elan Pharmaceuticals, used his experience with Elan's many R&D collaborations to help Mahley structure the deal. Freedman is also one of Mahley's advisors studying the different academic models for hybrid translational environments, looking at ways to fund the center to support more Gladstone programs, and building an industry-savvy development team.

Mahley and the Gladstone face many challenges while evolving the translational center. The driving force is his desire to see products emerge from Gladstone research and make a difference to patients. "I don't care if we ever spin out companies."

All of you biotech angel groups and cash-rich VCs might want to think about taking a closer look at the new center. Building products without building companies, operating in a cash-efficient setting, access to an engine for discovery . . . and all sitting close to a great ballpark and city! For a fraction of the cost to start a new company, you could be part of creating a perpetual motion machine with Gladstone.



BioWorld Today  January 16, 2007