The Combination of Two Genetic Variants Can Predict Response to Naltrexone in Individuals with Alcohol Use Disorder (AUD)

Description:

Technology: Researchers at MUSC have identified multiple gene variants that are critical for the response to opioid receptor antagonists, including naltrexone for AUD. First, recent work has further validated that carriers of OPRM1 asp40/ DAT10 variable number tandem repeat (VNTR) and asn40/ DAT9 variant carriers do better on naltrexone than other treatment groups (figure 1). These results suggest an epistatic balance of the opioid and dopamine systems may exist that should be taken into account in AUD trials.

In addition, a single nucleotide polymorphism (SNP) in another functional gene that controls dopamine system tone in the brain was also identified as playing a role in an individual’s clinical response to naltrexone. An interaction of the OPRM1 gene variants described above and this gene results in a significant prediction of efficacy (reduction in heavy drinking days) such that carriers of the OPRM1 A118G (asp40 allele) + wild-type gene and OPRM1 40asn allele with the SNP compared to other treatment groups (data not shown) do better on naltrexone. As a whole, genotyping this specific SNP can help inform AUD trials, aid in development of new pharmacotherapies and be used as a diagnostic test to identify AUD individuals that are most likely to benefit from opioid antagonists.

 

Overview: According to the National Institute for Alcohol Abuse and Alcoholism (NIAAA), 6.2 percent of adults in the US had an alcohol use disorder (AUD) in 2015. Medications available to treat AUD are not universally efficacious and in group studies have small to moderate effect sizes. Naltrexone is one of the few pharmacotherapies approved for AUDs and demonstrates consistent, albeit small to modest effect sizes for efficacy. A likely reason is that AUD is a heterogeneous illness with complex biology mediated by multiple brain systems, and genes and gene networks modulating those systems. There is growing interest in “personalized” treatment of alcohol use disorders i.e. precision medicine. Whether the putative mu opioid receptor polymorphism OPRM1 A118G SNP (asp40 allele) status influences naltrexone response is controversial, with retrospective studies being positive (Oslin, 2003, Anton, 2008) and one prospective study reportedly negative (Oslin, 2015). MUSC researchers had previously reported (Anton, 2012), in those not seeking treatment for AUD, that naltrexone effects on drinking were influenced by an interaction of the OPRM1 A118G SNP (asp40 allele) and VNTR variation (9 vs. 10 repeats) in the dopamine transporter gene (DAT1-SLC6A3). Now this discovery was replicated in a well conducted randomized clinical trial and a new gene controlling brain dopamine was also discovered to independently interact with the OPRM1 gene to predict naltrexone response.

 

Applications: Companion diagnostic, informing AUD treatment and AUD clinical trials, drug discovery

Advantages: Determine groups more likely to respond to opioid antagonists for multiple applications, including AUDs

Key Words: AUD, alcohol use disorder, alcoholism, pharmacotherapy, naltrexone, opioid antagonist, OPRM1, DAT1, SLC6A3, dopamine system, opioid system, alcohol, addiction

 

Background publications:

 

Schacht J., et al (2017) Predictors of naltrexone response in a randomized trial: Reward-related brain activation, OPRM1 genotype, and smoking status.  Neuropsychopharmacology. Available Online. 2017. PMID: 28409564

 

Anton RF., et al (2012) Naltrexone modification of drinking effects in a subacute treatment and bar-lab paradigm: influence of OPRM1 and dopamine transporter (SLC6A3) genes. ACER 36(11): 200-7.

 

Anton, R.F., et al (2008) An evaluation of μ-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: Results from the combined pharmacotherapies and behavioral interventions for alcohol dependence (COMBINE) study. Archives of General Psychiatry 65(2):135-144.

 

Oslin, D. W., et al (2003) A functional polymorphism on the μ -opioid receptor gene is associated with Naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546-1552.

 

Oslin, D. W., et al (2015) Naltrexone vs. Placebo for the treatment of alcohol dependence: A randomized clinical trial. JAMA Psychiatry 75(5):430-437.

 

Inventors: Ray Anton       

Patent Status:        Provisional filed 6.26.17              

MUSC-FRD Technology ID: P1753       

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Scott Davis
Sr Licensing Manager
MUSC Foundation for Research Development
843-876-1900
davissco@musc.edu
Inventors:
Raymond Anton
Keywords:
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