We are pleased to read the Letter from Dr. Brewer (1) on our paper in PNAS (2). In our manuscript, we only briefly discuss our current knowledge about aldehyde dehydrogenase 2 (ALDH2) inhibition therapy for the treatment of alcohol user disorder (AUD) due to space limitation. We greatly appreciate Dr. Brewer for elaborating on previous findings in the area of ALDH2 inhibition therapies that were tested both in patients and in animal models (1). It is true that the effects of ALDH2 genotype on alcohol-seeking behavior have been well documented (3) and many drugs that inhibit ALDH2 activities have been developed to treat AUD (4). For example, cyanamide (in the form of calcium carbimide citrate salt) can inhibit ALDH activity via its active metabolite and is still used therapeutically as an alcohol-aversive agent (Temposil) in Europe, Canada, and Japan (4). Disulfiram and cyanamide both are potent ALDH inhibitors and thus act as alcohol-drinking deterrents, through unpleasant experiences (e.g., nausea, tachycardia, flushing) produced by the accumulation of acetaldehyde in the blood of treated patients (4). Cyanamide is a second-line drug compared to disulfiram because of its capacity to produce greater liver damage compared with disulfiram (4). As described by Dr. Brewer, adjustments of the disulfiram therapy have shown promising results and supervised disulfiram treatment currently remains the most effective therapy in this drug class (5, 6); however, disulfiram therapy may generate side effects such as liver toxicity, neuropathies, and other adverse effects (7–9). In addition, although disulfiram has been repurposed as an anticancer agent (10), chronic disulfiram treatment may cause elevation of systemic and local acetaldehyde levels in alcoholics, thereby increasing the risk of cancer development.
By using liver-specific Aldh2 knockout mice and in vivo hepatocyte-Aldh2 expression knockdown, we demonstrated that a liver-targeted approach might be sufficient to reduce alcohol-seeking behavior while having limited effects on other metabolic parameters and global body functions (2). Major benefits from such strategies include limiting side effects on other organs, and cancer due to toxic acetaldehyde buildup in the general blood circulation and in other organs. Finally, such an approach may favor patients’ compliance to treatment by limiting the unpleasant effects of increased circulating acetaldehyde levels. Because numerous approaches could be used to specifically deliver a therapeutic agent to the liver and to the hepatocytes, such as modified liposomes, apolipoproteins, polymers, or viral vectors (11), it is feasible to specifically inhibit ALDH2 in the liver, and we hope our study may serve as a basis for the development of liver-targeted AUD treatment.
Acknowledgments
This work was supported by the intramural program of National Institute on Alcohol Abuse and Alcoholism, NIH (to B.G.).
Footnotes
The authors declare no competing interest.
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