Tissue-specific genes as an underutilized resource in drug discovery

Abstract

Tissue-specific genes are believed to be good drug targets due to improved safety. Here we show that this intuitive notion is not reflected in phase 1 and 2 clinical trials, despite the historic success of tissue-specific targets and their 2.3-fold overrepresentation among targets of marketed non-oncology drugs. We compare properties of tissue-specific genes and drug targets. We show that tissue-specificity of the target may also be related to efficacy of the drug. The relationship may be indirect (enrichment in Mendelian disease and PTVesc genes) or direct (elevated betweenness centrality scores for tissue-specifically produced enzymes and secreted proteins). Reduced evolutionary conservation of tissue-specific genes may represent a bottleneck for drug projects, prompting development of novel models with smaller evolutionary gap to humans. We show that the opportunities to identify tissue-specific drug targets are not exhausted and discuss potential use cases for tissue-specific genes in drug research.

Mild Methylenetetrahydrofolate Reductase Deficiency Alters Inflammatory and Lipid Pathways in Liver

“…Reduced methylation potential could enhance NAFLD progression, since progression can be limited by methyl‐donor supplementation . A recent meta‐analysis of liver biopsies from NAFLD patients showed decreased hepatic MTHFR expression associated with fibrosis progression . In our earlier study of wild‐type mice fed high folate, MTHFR protein was reduced and led to reduced SAM and PtdCho, with disturbed lipid metabolism and liver degeneration .…”

“…TT individuals have also been reported to have increased risk for steatosis (20 times higher for TT than CC in one report, although not all studies reached the same conclusion) . The high prevalence of cardiovascular disease in NAFLD, irrespective of genotype, may also relate to the aforementioned pro‐inflammatory or lipid changes.…”

“…NAFLD is associated with aberrant inflammation . Expression of many APPs was triggered by HFAT and/or MTHFR deficiency.…”

“…These individuals are hyperhomocysteinemic if their folate status is inadequate. 677TT has been associated with NAFLD in some studies but not others …”

“…Although progression of steatosis to NASH is reversible, progression of NASH toward cirrhosis is irreversible. The primary cause of mortality in NAFLD patients is cardiovascular disease …”