Reducing toxicity

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Stanford Reference: 07-020 Abstract Stanford researchers in the laboratory of Dr. Daria Mochly-Rosen have developed novel small molecules for modulating ALDH2 (mitochondrial aldehyde dehydrogenase-2). This new class of compounds was discovered using a new, sensitive high-throughput screening method, which is also included in this technology. ALDH2 plays an important role in reducing toxicity of both biogenic and xenogenic aldehydic compounds related to ischemic tissue damage or free-radical induced damage in an organ. Therefore, the ALDH2 activator compounds could potentially be used to preventively to reduce damage from ischemia, Alzheimer's disease, Parkinson's disease, alcohol-induced liver cirrhosis, or to overcome nitroglycerin insensitivity. Activator compounds were found to increase enzyme activity in in vivo assays, and in ex vivo and in vivo rat hearts. The ALDH2 activators could also be utilized for detoxification from ethanol, methanol or ethylene glycol. The compounds are effective in increasing activity of the wildtype enzyme and can also significantly restore the enzymatic activity in the ALDH2*2 mutant form that is present in an estimated 1 billion individuals worldwide (>40% of the East Asian population). In addition, ALDH2 inhibitor compounds were found. These could be used for cancer treatment, to increase tumor cell sensitivity to chemotherapy and radiation. Stage of Research The screening assay has been established and ALDH2 specific activators and inhibitors have been identified. Ex vivo and in vivo studies on rat hearts have demonstrated cardioprotection from ischemic injury if the treatment preceded the ischemic event. ALDH Portfolio This technology is a part of a larger portfolio that explores the potential applications of the ALDH multi-gene family.  Stanford Docket S03-268 describes ALDH2 activation and screening. Stanford Docket S08-073 describes structural studies and rational drug design methods. Stanford Docket S08-154 is comprised of ALDH2 knock-in mice. Stanford Docket S08-219 describes ALDH2 and ALDH1 activators. Stanford Docket S09-430 describes a collection of 48 ALDH cDNA and genomic clones for various ALDH isozymes. Stanford Docket S11-044 describes a novel ALDH3 activator and potential uses. Stanford Docket S11-154 describes modified N-oxide ALDH2 specific modulators. Stanford Docket S12-066 describes ALDH2 as a therapeutic target for pain. Applications   Therapeutic small molecule compounds for treatment of: ischemic myocardial injury in by pass surgery or heart transplantation heart failure cancer (by increasing tumor sensitivity to chemotherapy and radiation) Alzheimer's disease Parkinson's disease ethanol/acetaldehyde toxicity liver cirrhosis nitroglycerin sensitivity High-throughput screen - for compounds that modulate ALDH2 Stem cell therapeutics: adult - compounds could inhibit injury to cells after isolation and injection embryonic - ALDH2 is a marker for embryonic stem cells Advantages New class of compounds - small molecules that are likely to have low toxicity Specific - compounds affect the activity of ALDH2 and do not cross-react with ALDH1 Effects seen in wild type and mutant enzymes - the activator compounds can elevate ALDH2 enzymes encoded by the wild type allele as well as the E487K mutant allele (ALDH2*2) common in the Asian population.