Demonstrator 4: Drug Repurposing for FA

Question

What drugs might be used/repurposed to treat FA?

Background

• Defective ICL DNA Damage repair is driving mechanism behind FA
• Increase reactive aldehyde stress is a known contributor to FA
• Evidence in pre-clinical studies for efficacy of metformin in alleviate FA symptoms in mice

Queries / Evidence Paths

The queries/evidence paths below describe the types of information that might represent evidence to support the potential utility of a drug. Note here that the facts/criteria specified in each are not necessary or sufficient for a given solution. Rather, each represents a separate line of reasoning/evidence. Individually they may add support but not on their own be completely ‘convincing’. But collectively, if more than one is met, they could be convincing enough to support an assertion or hypothesis to be carried forward for further testing.

1. Drug targets genes associated with the FA disease (direct)
2. Drug targets genes that interact with (bind, genetic interaction, common pathways) genes associated with FA (direct)
3. Drug targets genes expressed in tissues affected by the disease (direct)
4. Drug is known to scavenge aldehydes (direct)
5. Drug shows structural similarity to known aldehyde scavengers (or potential scavengers like metformin that are believed to alleviate FA) (direct or reasoning/analysis)
6. Drugs known to target proteins/enzymes that have a positive effect on aldehyde production (direct)
7. Drug targets proteins acting in aldehyde processing pathways or processes (i.e. inhibits genes/processes that produce them, or stimulates genes/processes that eliminate them) (direct or reasoning/analysis)
8. Drug reduces expression of genes upregulated in FA (or increases expression of genes downregulated in FA) (reasoning/analysis)
9. Drugs used to treat diseases with phenotypic or pathophysiological similarity to FA (direct, then reasoning)
10. Drug shares side effects with other drugs used to treat/ alleviate FA.
11. Drug causes effects (intended or side effects) predicted to alleviate/counteract symptoms/phenotypes of FA (direct then reasoning/analysis)
12. Drugs that show similar biomarker profile signatures as metformin (e.g. in HTP cell-based drug screens measuring expression, metabolomics, PTM signatures, etc) (reasoning/analysis)
13. Drugs that show expression profiles similar to that is cells overexpressing aldehyde processing genes (e.g. Aldh2), or 'opposite' of those where such genes are knocked down.
14. Drug targets genes that have functional similarity with genes involved in phenotypically similar diseases to FA.