Mitochondrial aldehyde dehydrogenase 2*2 (ALDH2*2) knock-in gene targeting mice-an experimental model for a prevalent human genetic disorder in East Asians

A common dominant negative allele, Aldh2*2, exists in the human population. The ALDH2*2 mutant retains only about 1-3% of the enzymatic activity of a corresponding wild-type ALDH2 and affects >40% of the East Asian population (including Japanese, Chinese, Taiwanese and Koreans with an estimated > 1 billion affected individuals). Reduced ALDH2 activity has been associated with a range of human metabolic disorder and diseases. Accumulation of biogenic/xenogenic aldehydes in ALDH2*2 individuals are known to cause sensitivity to alcohol intoxication (hangover), ischemic tissue damage, free-radical induced damage in an organ, such as acute myocardial infarction, heart failure, stroke, Alzheimer disease, Parkinson's disease, other neurodegenerative diseases, alcohol-induced liver cirrhosis, cancers of upper digestive track, insensitivity to nitroglycerin treatment, and hyper-sensitivity to certain drug metabolism.

This invention creates an identical genetic model for animal research specifically for human subjects carrying the ALDH2*2 allele. No such genetically engineered animal exists currently. This mutation affects an estimated >1 billion people.
This invention offers an innovative idea for testing of drug/pharmaceuticals sensitivity and treatment in human ALDH2*2 carriers. Currently the usage of most of the prescribed pharmaceuticals does not take into account of human genetic polymorphism. This is an important aspect in research and application of pharmaco-genetics. We also provide in vitro data to indicate that ALDH2*2 enzyme may be sensitive to some drugs that are previously unknown or have not yet been described in the literature.