A generalizable pre-clinical research approach for orphan disease therapy

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.

Figure 1

Normalizing the pathogenic imbalance. Protein levels and/or activity outside of the physiological normal range usually underlie a monogenic disease. Therapeutic approaches may involve normalizing this imbalance by enhancing the mRNA, protein, or protein activity in disorders caused by LOF mutations and moderating the mRNA, protein, or protein function excess observed in GOF mutations.

Figure 2

Pharmacologically responsive therapeutic targets. mRNA (and thus proteins) which are both pharmacologically responsive and disease modulating represent potential therapeutic targets.

Figure 3

Orphan disease translational pathway. Schematic of possible orphan disease therapeutic avenues depending on nature of mutation, disease mechanism, and information mined from existing datasets. *In silico screen possible. **Computer based drug identification/design possible.

Figure 4

Therapeutic approaches based on small molecules and ASOs. Small molecules have the potential to regulate the expression of genes. Haploinsufficient or partially functioning proteins can be upregulated to compensate for the reduced activity. If a non-functional mutated gene has a homolog with overlapping function, the homolog can be upregulated to partly compensate for the non-functioning protein (termed rescuing paralog). ASOs have the potential to modify pre-mRNA splicing or expression. Cryptic splice sites caused by mutations can be blocked to correct splicing. Conversely, genes with overexpression or with gain-of-function mutations can be downregulated.