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Innovations in the ability to probe and better understand biologic systems during the past 30 years1-3 have enabled the medical community to develop new restorative agents and alter the course of many life-shortening diseases. 4, 5 Naturally success, bridging the gap between promising laboratory observations and the development of effective therapies remains risky and expensive, with fewer than 1 in 10, 1000 early translational programs effectively obtaining Food and Drug Administration (FDA) authorization, at a cost of almost $1 billion. 6 Most therapeutic development fails in the preclinical phase, which is sometimes described as the "valley of dying. "7
For this reason and because therapies for a few conditions will have a limited eventual market value, the pharmaceutical industry has recently been hesitant to initiate early-stage programs to take care of so-called orphan diseases. In recognition of a critical need, federal agencies have developed programs to catalyze innovation and reduce obstacles to early advancement new therapies. 8 In the past two decades, disease-focused foundations also have developed a new strategy to bridging this preclinical gap. In a process known as venture philanthropy, such foundations have formed relationships with industry and federal government agencies to talk about the financial risk of therapeutic development, shorten the early translational pipeline, and advance research with "a give attention to individual, not financial, return. "9 In addition, foundations and their academic partners have accelerated early development by providing access to patient populations for clinical studies and assistance from disease-specific experts in study design, which has helped in bridging the gap in therapeutic development.
In this review, we will concentrate on about three diseases -- cystic fibrosis, multiple myeloma, and type 1 diabetes mellitus -- to illustrate how collaborations among academic institutions, fundamentals, and industry partners have evolved to address the therapeutic challenges of these conditions.
CYSTIC FIBROSIS
Within 1989, the discovery of the gene that will cause cystic fibrosis and the cystic fibrosis transmembrane conductance regulator (CFTR) protein10, eleven greatly increased interest within the scientific community in this life-shortening genetic disease, which impacts approximately seventy, 000 patients worldwide. Along with support from the Cystic Fibrosis Foundation (CFF) and the National Institutes of Health (NIH), researchers swiftly expanded knowledge about the biogenesis, maturation, and perform of CFTR, a controlled epithelial anion channel12; such knowledge provided the necessary scientific framework for the development of therapeutic goals. In addition, an international consortium13 determined more than 1700 mutations and identified genotype-phenotype correlations with standard case definitions, 14 which enabled a precision-medicine strategy to therapeutic development. In the 1990s, attempts were made to treat cystic fibrosis by gene-replacement remedy delivered to airway epithelia. Although early in vitro15 and in vivo studies16 provided proof of concept, many barriers, including a powerful host immune response, were encountered. 17 These barriers ended such initial scientific development programs.
In the decade following the discovery of the cystic fibrosis gene, scientific knowledge expanded but did not lead to a remedy that corrected CFTR function. In 1999, the CFF launched the Therapeutic Development Program (TDP) to attract both academic and industry partners and start high-throughput screening for CFTR modulators. 18, 19 The CFF embraced the concept of venture philanthropy9, 20 to raise the interest of industry in an orphan disease. However, the success of the TDP was centered on a lot more than financial support. 21 The program created a cultural change that allowed the CFF, academic clinicians and experts, federal agencies (the NIH and FDA), and industry to create a strong partnership with common goals and timelines.

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