Abstract
With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.
Highlights
Single gene disorders, which typically result from mutations having severe effects on gene function, are of particular importance in pediatrics
The curated Online Inheritance in Man (OMIM) human genetics database currently lists over 3300 genes for which DNA sequence variants have been associated with human disease [3]
Genetic disorders of high penetrance are typically caused by mutations that result in i) loss-of-function (LOF), i.e., a reduction in the level and/or activity of a given protein, usually seen in recessively inherited disorders or ii) gain-of-function (GOF), i.e., an increase in protein level and/or activity with the introduction of a novel pathological function often associated with activation of a pathway, usually seen in dominantly inherited disorders [4]
Summary
Single gene disorders, which typically result from mutations having severe effects on gene function, are of particular importance in pediatrics. The same in silico screening approaches can be used to identify agents that upregulate mRNA encoding mutated proteins with residual function, such as seen in milder variants of a recessive disease; given the low levels of protein frequently observed in these disorders, even a modest increase in activity might be anticipated to have a clinically appreciable effect. High content cellular screening for compounds leading to correction of mutated trafficking anomalies, may be one robust route to active pharmacologic chaperones given the cost of these approaches the preferable scenario would include a relatively common or recurrent causal mutation (which are often seen in local and even large founder populations) and a good in silico lead into a compound class In this context, RNAi approaches with cellular screens for protein localization may identify currently unappreciated genes that would have a broad impact on folding of mutated polypeptides, irrespective of specific mutation or even particular protein involved.
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