Drug repositioning for orphan diseases

Department of Computer Science, University of Cincinnati, OH, USA.
Briefings in Bioinformatics (Impact Factor: 9.62). 04/2011; 12(4):346-56. DOI: 10.1093/bib/bbr021
Source: PubMed


The need and opportunity to discover therapeutics for rare or orphan diseases are enormous. Due to limited prevalence and/or commercial potential, of the approximately 6000 orphan diseases (defined by the FDA Orphan Drug Act as <200 000 US prevalence), only a small fraction (5%) is of interest to the biopharmaceutical industry. The fact that drug development is complicated, time-consuming and expensive with extremely low success rates only adds to the low rate of therapeutics available for orphan diseases. An alternative and efficient strategy to boost the discovery of orphan disease therapeutics is to find connections between an existing drug product and orphan disease. Drug Repositioning or Drug Repurposing--finding a new indication for a drug--is one way to maximize the potential of a drug. The advantages of this approach are manifold, but rational drug repositioning for orphan diseases is not trivial and poses several formidable challenges--pharmacologically and computationally. Most of the repositioned drugs currently in the market are the result of serendipity. One reason the connection between drug candidates and their potential new applications are not identified in an earlier or more systematic fashion is that the underlying mechanism 'connecting' them is either very intricate and unknown or indirect or dispersed and buried in an ever-increasing sea of information, much of which is emerging only recently and therefore is not well organized. In this study, we will review some of these issues and the current methodologies adopted or proposed to overcome them and translate chemical and biological discoveries into safe and effective orphan disease therapeutics.

Download full-text


Available from: Ranga CHANDRA Gudivada, Nov 03, 2014
74 Reads
  • Source
    • "The previous discussion explains why drug repositioning constitutes a key strategy in the field of drug discovery and development for orphan diseases, where there is an obvious need of collaborative public-private partnerships [20] [22] [90] [91]. Several initiatives such as WHO Special Programme for Research and Training in Tropical Disease, the Medicines for Malaria Venture, the Global Alliance for TB Drug Development, Drugs for Neglected Diseases and the Open Source Drug Discovery initiative have recognized drug repositioning as an attractive option to provide low-cost access to medications in developing countries [92]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug repurposing/reprofiling has attracted considerable attention during the last decade. The object of such approach is to discover second or further medical uses of known chemicals, i. e. targeting existing, withdrawn or abandoned drugs, or yet to be pursued clinical candidates to new disease areas. Recently (2011-2012), the US and UK governments launched public-private joint initiatives towards finding new uses of previously shelved compounds (drug rescue). While in the past repurposing emerged from serendipitous findings and/or from rational exploitation of drug side-effects (e.g. sildenafil, aspirin), the current tendency in the drug development field focuses on knowledge-based drug repurposing, particularly, computer-aided repositioning approaches. The present chapter reviews different cheminformatic and bioinformatic applications, as well as high-throughput literature analysis, oriented to the discovery of new medical uses of known drugs. Applications of such strategies to the discovery of innovative medications for neglected or rare diseases are discussed. Finally, we also review publicly available resources (e.g. chemical libraries) valuable for reprofiling.
    Frontiers in Computational Chemistry (Vol. 1), Edited by Zaheer-ul-Haq, J. D. Madura, 01/2015: chapter 2: pages 44-81; Bentham Science., ISBN: 978-1-60805-865-5
  • Source
    • "Programmes to identify new clinical activities of existing medicines have been conducted in many therapeutic areas, such as oncology [15] and for orphan diseases [16], where there is often an extremely high and specific unmet medical need. Approaches have also been successful in infectious disease, such as tuberculosis [17], schistosomiasis [18] and onchocerciasis [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against of Plasmodium falciparum blood stages. Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR(R)I dye DNA staining assay (3D7, K1 or NF54 strains); [3H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low muM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D70087/N9 huSCID 'humanized' mouse model. Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model. Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at muM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
    Malaria Journal 04/2014; 13(1):143. DOI:10.1186/1475-2875-13-143 · 3.11 Impact Factor
  • Source
    • "Traditionally, second medical uses emerged from intelligent exploitation of approved or investigational drugs side effects (e.g., to exploit the aspirin antiplatelet effect to prevent heart attacks and strokes or the use of sildenafil to treat erectile dysfunction). Lately, however, knowledgebased , rational drug repositioning (chemoinformatics-and bioinformatics-based and others) has gained attention [16– 19] and is being increasingly used to aid in discovering novel treatments for rare, neglected, and poverty-related conditions [20] [21] [22] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cruzipain (Cz) is the major cysteine protease of the protozoan Trypanosoma cruzi, etiological agent of Chagas disease. A conformation-independent classifier capable of identifying Cz inhibitors was derived from a 163-compound dataset and later applied in a virtual screening campaign on the DrugBank database, which compiles FDA-approved and investigational drugs. 54 approved drugs were selected as candidates, 3 of which were acquired and tested on Cz and T. cruzi epimastigotes proliferation. Among them, levothyroxine, traditionally used in hormone replacement therapy in patients with hypothyroidism, showed dose-dependent inhibition of Cz and antiproliferative activity on the parasite.
    The Scientific World Journal 01/2014; 2014:279618. DOI:10.1155/2014/279618 · 1.73 Impact Factor
Show more