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2 The State of the Science
Pages 7-16

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From page 7...
... Academia, industry, and government stakeholders each have a distinct set of concerns regarding the state of the science for drug repurposing, but workshop speakers emphasized that because each of those groups has its own strengths, if they work together it can increase the likelihood of the successful translation of a repurposed drug. Many of the examples cited by individual speakers in this session -- and throughout the workshop -- involved rare diseases, which have been a focus of re 7
From page 8...
... INDUSTRY REPURPOSING EFFORTS Three strategic elements are key to drug repositioning, said Don Frail, vice president of science at AstraZeneca. The first is having access to compounds, which typically involves access not just to the compound itself but to all of the information associated with that compound, such as safety data and clinical study reports.
From page 9...
... Repositioning can also raise complex issues about regulatory filings, pricing, and other considerations, all of which can serve as deterrents to project teams. For example, in collaborations an investigator will often request updated clinical regulatory documents, such as an investigational new drug application, and it can be time-consuming to collect all of the updated information and make the changes to the existing document, Frail said.
From page 10...
... . RARE DISEASES According to the NIH Office of Rare Diseases Research, about 6,800 diseases with limited therapeutic options affect between an estimated 25 and 30 million Americans.
From page 11...
... POTENTIAL OPPORTUNITIES FOR DRUG DISCOVERY Mendelian disorders represent a great opportunity in drug discovery, said Harry Dietz, the Victor A McKusick professor of pediatrics, medicine, and molecular biology and genetics at the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine.
From page 12...
... Mendelian disorders facilitate the identification of genetic modifiers in people and in experimental models, which can lead to surprising and appealing treatment strategies. Genetically defined animal models of rare diseases allow for genetic or pharmacologic perturbations that allow mechanisms to be refined.
From page 13...
... Nine clinical trials of losartan in Marfan syndrome are ongoing, and the two whose outcomes have been reported have produced promising results, Dietz said. He and his colleagues have focused on treating a subset of children with the most severe and rapidly progressive form of Marfan syndrome; these children normally exhibit unrelenting aortic root growth despite maximal treatment with beta blockers and/or angiotensinconverting enzyme (ACE)
From page 14...
... "These data suggest that oxytocin antagonists such as atosiban, which is approved for use in pre-term labor in other countries, may find utility in the treatment of aortic aneurysm and aortic tear," Dietz said. Genetic Modifiers In five exceptional families that showed discrete intrafamilial variation in phenotypic severity, where half of the mutation carriers died because of aortic dissection by the age of 15 and the other half had no vascular manifestation of Marfan syndrome at the age of 60, linkage analysis revealed a protective locus on human chromosome 6 with a logarithm-of-odds (LOD)
From page 15...
... For example, compounds related to those effective in Marfan syndrome have been shown to attenuate vascular disease in multiple TGF-beta vasculopathies, including common conditions such as bicuspid aortic valve with aneurysm, which affects 1 percent of the general population, he said. TGF-beta-induced suppression of muscle regeneration also contributes to both rare and common myopathic states, and the angiotensin receptor blockers are protective in mouse models of Duchenne muscular dystrophy or immobility associated with muscle atrophy and weakness (Ennen et al., 2013)


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