Gene Therapy for Cocaine Use Disorder

Overseen By Beth Martin, RRT

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: W. Michael Hooten

Disqualifiers: HIV, Hepatitis, Pregnancy, Morbid obesity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy to help individuals with cocaine use disorder remain in remission. The treatment, AAV8-hCocH, uses a viral vector to deliver a gene that produces an enzyme called cocaine hydrolase, which breaks down cocaine to prevent the usual high. The trial aims to ensure the treatment's safety. It may suit adults diagnosed with cocaine use disorder who are not currently seeking treatment and wish to avoid cocaine. Participants should be in good general health and willing to attend regular clinic visits. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team to get a clear answer.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the gene therapy AAV8-hCocH is generally safe in early tests. Studies with mice found it was well-tolerated and did not cause harmful effects. The treatment even helped protect against cocaine's effects. Another study found that the AAV8 viral vector, used to deliver the gene, did not cause negative effects. These findings suggest the treatment is safe and might be effective at the tested doses. However, as this is a Phase 1 trial, researchers are primarily focused on ensuring its safety for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cocaine use disorder, which often involve behavioral therapy and medications like disulfiram and naltrexone, AAV8-hCocH acts through a novel gene therapy approach. This treatment uses an adeno-associated virus (AAV8) to deliver a human enzyme called hCocH, which is designed to break down cocaine in the bloodstream, reducing its psychoactive effects. Researchers are excited about this approach because it directly targets the metabolism of cocaine, potentially offering a one-time treatment that could provide long-lasting results, unlike current options that require ongoing administration.

What evidence suggests that this gene therapy might be an effective treatment for cocaine use disorder?

Research has shown that the AAV8-hCocH gene therapy might help treat cocaine addiction. This therapy uses a gene that produces an enzyme called cocaine hydrolase, which breaks down cocaine into harmless substances. In studies with mice, those treated with AAV8-hCocH experienced less tissue damage from cocaine than untreated mice. This suggests the treatment could lessen cocaine's harmful effects. Additionally, research has found the therapy to be safe and well-tolerated at reasonable doses. In this trial, participants will receive one of three different dose levels of AAV8-hCocH to evaluate its effectiveness and safety in reducing cocaine cravings and damage in people. ^{1 2 3 4 5}

Who Is on the Research Team?

Michael Hooten, M.D.

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

Adults aged 18-65 with a diagnosis of cocaine use disorder in remission can join this trial. They must be motivated to stay off cocaine, able to attend regular clinic visits, and have normal heart rhythms and general health. Pregnant or breastfeeding individuals, those with obesity (BMI > 40), immunity to AAV8 capsid, HIV/hepatitis, kidney issues (Creatinine ≥ 1.5 mg/dL), or other disqualifying conditions cannot participate.

Inclusion Criteria

DSM-5 diagnosis of cocaine use disorder in sustained remission as confirmed by the PI's review of the medical record

Show a baseline EKG that demonstrates normal sinus rhythm and conduction without clinically significant abnormalities or arrhythmias

Have hematology, chemistry, kidney and liver function laboratory tests that are within (+/- 10%) of the current Mayo Clinic standardized normal values

Exclusion Criteria

Any disease or mental health condition at the physician's discretion that would prevent the subject from fully complying with the requirements of the study. The physician may exclude subjects with active alcohol abuse, other substance abuse or positive urine toxicology screen for substances of abuse

I am not pregnant or breastfeeding and agree to use birth control during the study.

My BMI is over 40.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time IV administration of AAV8-hCocH at varying dose levels

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and enzyme expression levels after treatment

7 weeks

Multiple visits (in-person)

Long-term follow-up

Participants are monitored for long-term safety and effectiveness

24 months

What Are the Treatments Tested in This Trial?

Interventions

• AAV8-hCocH

Trial Overview The trial is testing a new gene therapy using AAV8-hCocH for adults who are not seeking treatment but want to maintain their remission from cocaine use. This gene helps break down cocaine quickly which may reduce its pleasurable effects.

How Is the Trial Designed?

Group I: AAV8-hCocH dose level 3: 6e12vg/kg Experimental Treatment 1 Intervention

Cohort 3: Participant receives one-time IV administration of medium dose 6e12vg/kg of AAV8-hCocH, with 7 week of follow-up after dose

Group II: AAV8-hCocH dose level 2: 4e12vg/kg Experimental Treatment 1 Intervention

Cohort 2: Participant receives one-time IV administration of medium dose 4e12vg/kg of AAV8-hCocH, with 7 week of follow-up after dose

Group III: AAV8-hCocH dose level 1: 2e12 vg/kg Experimental Treatment 1 Intervention

Cohort 1: Participant receives one-time IV administration of low dose 2e12 vg/kg of AAV8-hCocH, with 7 week of follow-up after dose

Who Is Running the Clinical Trial?

W. Michael Hooten

Lead Sponsor

Trials

1

Recruited

10+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study involving mice treated with high doses of cocaine, pretreatment with a viral vector delivering cocaine hydrolase effectively protected against cocaine-induced prolongation of the QT interval, a serious heart condition.

The viral delivery of cocaine hydrolase showed no intrinsic cardiac toxicity, indicating it is a safe therapeutic option for mitigating the cardiac risks associated with cocaine addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice. Murthy, V., Reyes, S., Geng, L., et al.[2018]

AAV8-hCocH gene therapy, which uses a viral vector to help metabolize cocaine into harmless by-products, showed no adverse effects in both cocaine-experienced and naive mice, indicating a strong safety profile for this treatment approach.

Mice treated with AAV8-hCocH had significantly less tissue damage compared to those that received cocaine without the gene therapy, suggesting that this method could effectively reduce the harmful effects of cocaine use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice. Chen, VP., Gao, Y., Geng, L., et al.[2021]

In a study involving mice, gene transfer of human butyrylcholinesterase (BChE) using viral vectors showed no adverse physiological or metabolic effects, even at high doses, indicating a strong safety profile for this potential therapy.

The treatment not only maintained normal physiological parameters but also protected the mice from the negative effects of cocaine, suggesting that BChE gene therapy could be a promising approach for treating cocaine addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice. Murthy, V., Gao, Y., Geng, L., et al.[2021]

Site-directed mutagenesis has created new enzymes that can rapidly break down cocaine, and researchers are exploring the potential of using gene therapy to deliver these enzymes directly to the brain to reduce cocaine's effects and addiction risk.

In a study where vectors were injected into the nucleus accumbens of rats, significant increases in cocaine-hydrolyzing enzyme activity were observed, suggesting that this method could effectively limit cocaine's access to the brain and support future addiction treatment research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viral transduction of cocaine hydrolase in brain reward centers. Gao, Y., Brimijoin, S.[2019]

Gene transfer of a modified mouse cocaine hydrolase (mCocH) showed a significant increase in enzyme activity and sustained expression in mice for over a year without triggering an immune response, indicating its potential for treating cocaine addiction.

The advanced viral vector used for gene transfer not only enhanced cocaine hydrolase activity dramatically but also protected mice from severe behavioral and physiological effects of cocaine overdose, suggesting a promising therapeutic approach for addiction management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer of mutant mouse cholinesterase provides high lifetime expression and reduced cocaine responses with no evident toxicity. Geng, L., Gao, Y., Chen, X., et al.[2021]

Transplanting skin cells modified to produce an enhanced form of butyrylcholinesterase in mice significantly reduces cocaine-seeking behavior and protects against cocaine overdose, suggesting a novel approach to treating cocaine addiction.

This study highlights the potential of cutaneous gene therapy as a long-term solution for drug abuse by enabling the body to eliminate cocaine more effectively, marking a promising direction for future therapeutic interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose. Li, Y., Kong, Q., Yue, J., et al.[2023]

Engineered versions of human butyrylcholinesterase (BChE) can effectively break down cocaine in the bloodstream, reducing its effects on the brain and diminishing addictive behaviors.

Advancements in anti-cocaine antibodies and vaccines, combined with gene transfer methods for delivering these treatments, show promise for addressing cocaine addiction, though potential risks must be carefully considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interception of cocaine by enzyme or antibody delivered with viral gene transfer: a novel strategy for preventing relapse in recovering drug users. Brimijoin, S.[2021]

Gene transfer of a cocaine-hydrolyzing enzyme (CocE) significantly reduced cocaine's effects in brain reward centers, as shown by a 25,000-fold increase in cocaine hydrolase activity after intravenous delivery in rats.

Rats treated with the active CocE vector showed minimal FosB expression in response to cocaine, indicating a protective effect against cocaine-induced changes, similar to rats that had never been exposed to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lasting reduction of cocaine action in neostriatum--a hydrolase gene therapy approach. Gao, Y., Brimijoin, S.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6985763/

Systemic Safety of a Recombinant AAV8 Vector for Human ... These results indicate that a liver-directed AAV8-hCocH gene transfer at reasonable dosage is safe, well tolerated, and effective.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04884594

NCT04884594 | AAV8-hCocH for Cocaine Use Disorder The purpose of this study is to test the safety of a novel gene viral vector treatment for adults with cocaine use disorder-sustained remission. This gene ...

3. mayo.edu mayo.edu/research/clinical-trials/cls-20514649

A Study to Evaluate AAV8-human Cocaine Hydrolase to ... The purpose of this study is to see if an experimental agent, when given to subjects who wish to abstain from cocaine, will decrease their craving for cocaine ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31650869/

Systemic Safety of a Recombinant AAV8 Vector for Human ... These results indicate that a liver-directed AAV8-hCocH gene transfer at reasonable dosage is safe, well tolerated, and effective.

5. withpower.com withpower.com/trial/phase-1-cocaine-related-disorders-8-2021-25ef8

Gene Therapy for Cocaine Use Disorder Mice treated with AAV8-hCocH had significantly less tissue damage compared to those that received cocaine without the gene therapy, suggesting that this method ...