Academics Want Collaboration with Pharma

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By Kevin Davies, BIO-IT WORLD

Ten years ago, Gillian Bates, PhD — who is currently head of the Neurogenetics Research Group at King’s College London (London, U.K.) — was part of the international consortium that identified the gene for Huntington’s disease (HD), an incurable hereditary neurodegenerative disorder. Now, her lab is one of a growing wave of academic groups turning their attention to the development of small-molecule drugs.

“Only by the community working together — the academic community and small biotechs — will we be able to improve the drug-discovery pipeline to help treat diseases such as HD,” Bates said.

HD is caused by the bizarre expansion of a tract of repetitive DNA in a gene that codes for Huntington, a protein found in the cell bodies of neurons. If the gene tract expands beyond a certain length (coding for 36 glutamine amino acids), pathogenesis ensues, with patients inexorably developing motor and behavioural abnormalities.

“Patient brains atrophy and shrink,” Bates explained. This reaction is coincident with deposits of protein aggregates in the nucleus. Ten to 15 years from symptom onset, patients inevitably die.

In 1996, Bates’s team developed the best mouse model for the disease, and is using these mice to screen various small-molecule drugs, working in collaboration with Aton Pharma Inc. (recently acquired by Merck & Co. Inc. of Whitehouse Station, N.J.). The goal is to identify molecules that could postpone the age of onset of the disease, halt or reverse the symptoms, and/or slow progression of the disease.

The most promising candidate so far is an HDAC (histone deacetylase) inhibitor called SAHA, which is already in clinical trials for cancer. HDAC inhibitors regulate gene expression, which appears to go awry in HD. Bates has presented mouse data showing that a dose of 100 milligrams per kilogram per day led to a dramatic improvement in various physiological tests. Sodium butyrate is another candidate, she says.

Alliance in China
A further example of academia working closely with industry was presented by Zhu Chen, PhD, director of the Chinese National Human Genome Center at Shanghai (Shanghai, China). Chen and colleagues have found that ATRA (all-trans retinoic acid) is effective in treating forms of acute promyelocytic leukemia, by triggering differentiation and cell death. Other patients are responding well to combination therapy with ATRA and arsenic trioxide (ATO). Chen says that this approach combined with chemotherapy has resulted in “the first curable human leukemia” — work that Chen will detail soon in an inaugural article in the Proceedings of the National Academy of Sciences as a newly elected foreign member.

Chen is also collaborating with Novartis AG (Basel, Switzerland) to begin trials for a combination therapy for chronic myelogenous leukemia. Noting that “the cost of Gleevec® is too high for developing countries,” Chen has found that ATO synergizes the effects of Novartis’s oncology drug Gleevec on cell death. Even more effective is arsenic sulphide, which can be orally administered and exhibits fewer side-effects than ATO.

“We are fortunate to get support from Novartis (AG) to start a clinical trial using Gleevec and arsenic sulphide,” Chen said. “Chemical genetics is a driving force for functional genomics and drug discovery in the 21st century,” he added.

Collaboration Essential
Dr. Frank L. Douglas, PhD, member of the management board and executive vice-president for Drug Innovation and Approval at Aventis SA (Strasbourg, France), temporarily put aside the debate over the takeover of his company by Sanofi-Synthélabo SA (Paris, France) to present a vision of pharma in 2014 that will put a “profound focus on the patient.”

“We are in the middle of the genomic era,” Douglas said. “It is a real disservice to refer to the first few decades of this century as the post-genomic era. We are in our adolescence.”

Douglas, who is based in Frankfurt, Germany, also echoes the collaborative theme with academia.

“Drug discovery will become a concerted attack on diseases for the benefit of the patient — no single pharma or biotech can do it all,” he said.

Highlights that Douglas predicts for the world of pharma in 10 years include the following:

patients will be assessed for individual risks
improved molecular understanding of disease
new technologies will assign function to targets
compounds will be designed and assayed in silico
combination therapy
pharmacogenomic stratification of patients
Douglas also echoed the sentiments of the director of the National Cancer Institute (NCI) (Bethesda, MD), Dr. Andrew C. von Eschenbach, who has promoted the idea that cancer could become a manageable, chronic disease by 2015. Eschenbach has made that objective a goal of the NCI.