Disulfiram for Retinal Degeneration

Overseen By Debarshi Mustafi, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Washington

Must not be taking: Anticoagulants, others

Disqualifiers: Diabetes, Psychosis, Hypothyroidism, others

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Aberrant retinoic acid signaling driven by the degenerating outer retina leads to pathological changes to the inner retina. The resulting hyperactivity of retinal ganglion cells leads to further diminution of the remaining vision in those afflicted with inherited retinal diseases. Inhibition of this pathway has led to improved visual function in murine models of retinal degeneration. This can be accomplished in humans with the FDA-approved irreversible inhibitor of aldehyde dehydrogenases, disulfiram.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot be on anticoagulant therapy or other medications that may be affected by disulfiram. It's best to discuss your current medications with the study team.

Is disulfiram generally safe for humans?

Disulfiram, commonly used to treat alcoholism, is generally safe for humans and has been used for about 50 years with negligible adverse effects compared to traditional cancer treatments. It is important to note that it can cause significant effects at the cellular level, but it does not cause symptoms in people who do not consume alcohol. ^{1 2 3 4 5}

How does the drug Disulfiram differ from other treatments for retinal degeneration?

Disulfiram is unique because it is being repurposed from its original use as a treatment for alcohol dependence to potentially address retinal degeneration by inhibiting the accumulation of toxic pigments in the retina, which is a novel approach compared to other treatments that focus on neuroprotection or inflammation suppression. ^{6 7 8 9 10}

Research Team

Debarshi Mustafi, MD, PhD

Principal Investigator

University of Washington

Eligibility Criteria

Adults over 18 with a clinical diagnosis of inherited retinal degeneration, who have relatively good vision (20/40 or better) and can see within 10 degrees centrally. Participants must not drink alcohol for the duration of the study plus two weeks before and after. They should also have normal levels of albumin, total protein, ALT, AST, and ALP.

Inclusion Criteria

You have a narrow field of vision of 10 degrees in the center.

Your AST blood test result is below 40 IU/L.

I am 18 or older with a diagnosed inherited eye condition, possibly supported by genetic testing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive disulfiram or placebo to evaluate effects on retinal sensitivity and visual function

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Disulfiram
• Placebo

Trial Overview The trial is testing Disulfiram (250 mg), an FDA-approved drug that may improve visual function by inhibiting a pathway linked to vision loss in retinal degeneration. It's compared against a placebo to evaluate its effectiveness in humans.

Participant Groups

Group I: Disulfiram Active Control 1 Intervention

Disulfiram medication

Group II: Placebo Placebo Group 1 Intervention

Placebo medication

Disulfiram is already approved in United States, European Union for the following indications:

Approved in United States as Antabuse for:

• Alcohol dependence

Approved in European Union as Antabuse for:

• Alcohol dependence

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Findings from Research

Disulfiram (DSF) and its metabolite diethyldithiocarbamate (DDTC) were evaluated against 30 types of bacteria, with DDTC showing notable antibacterial activity specifically against Bacillus anthracis.

The study suggests that while DSF's metabolites do not significantly enhance its antibacterial properties, DDTC can boost the effectiveness of DSF, indicating its potential as an antibiotic adjuvant for treating resistant staph infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibacterial activity of disulfiram and its metabolites. Frazier, KR., Moore, JA., Long, TE.[2019]

Disulfiram, a drug traditionally used to treat alcoholism, has shown promising anticancer activity, particularly in suppressing liver metastases from ocular melanoma, making it a potential new treatment option.

This drug is not only inexpensive and widely available, but it also has a favorable safety profile compared to conventional cancer treatments, with negligible adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? Cvek, B., Dvorak, Z.[2015]

Disulfiram (Antabuse) is an effective part of alcoholism treatment when combined with counseling and support, and its effectiveness is enhanced by supervised administration to ensure patient compliance.

The disulfiram-ethanol reaction (DER) is crucial for demonstrating the drug's effectiveness, serving as a positive reinforcement for sobriety, and the therapy is generally safe with few serious side effects, although there are specific concerns regarding hepatotoxicity, especially in women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How to get the best out of antabuse. Kristenson, H.[2013]

In a double-blind trial involving 15 HIV-positive men, disulfiram was administered at doses of 100 mg or 400 mg daily for 4 weeks, but it did not show any significant effects on immune function or overall health.

Despite its potential as an immunomodulating agent, disulfiram did not improve immunological, hematological, or clinical outcomes in participants with low CD4 counts or impaired lymphocyte response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of immunomodulating effect of disulfiram on HIV positive patients. Hørding, M., Gøtzsche, PC., Bygbjerg, IC., et al.[2019]

Disulfiram (Antabuse) effectively inhibits the RNA-dependent DNA polymerase of Rous sarcoma virus, preventing it from causing malignant transformation in chick embryo cells, highlighting its potential anti-cancer properties.

Disulfiram induces the synthesis of specific proteins in normal cells and shows a greater impact on DNA synthesis compared to RNA and protein synthesis, suggesting it may influence cellular processes beyond its use in treating alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of antabuse (disulfiram) on Rous sarcoma virus and on eukaryotic cells. Levinson, W., Mikelens, P., Oppermann, H., et al.[2019]

There is currently no FDA-approved treatment for the dry form of age-related macular degeneration (AMD), which is a leading cause of blindness, and it is linked to the accumulation of toxic lipofuscin pigments in retinal pigment epithelium (RPE).

Inhibiting the production of these harmful lipofuscin bisretinoids, such as A2E, through various pharmacological strategies, including enzyme inhibitors and vitamin A analogs, presents a promising approach for developing treatments for dry AMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment. Petrukhin, K.[2021]

There is a significant need for new treatments for dry age-related macular degeneration (AMD), and repurposing existing FDA-approved drugs presents a promising strategy.

Several classes of drugs, including GPR-143 agonists, anti-diabetic medications, mitochondrial activators, and serotonin pathway drugs, are being explored for their potential to reduce AMD diagnosis, highlighting the innovative approach of using existing medications for new therapeutic purposes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing Drugs for Treatment of Age-Related Macular Degeneration. Francisco, SG., Rowan, S.[2023]

In a study of 97 patients with inactive tuberculous chorioretinitis, retinalamine injections significantly improved retinal function, leading to a 66.3% increase in visual acuity and enhanced electrophysiological activity in the majority of cases.

Retinalamine treatment also slowed the progression of age-related cataracts, preventing vision loss in a high percentage of patients over four years, demonstrating its potential as an effective bioregulator in ocular tuberculosis management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with the peptide bioregulator retinalamine in patients with tuberculosis of the organ of vision]. Aleksandrov, EI., Aleksandrova, TE.[2008]

Emerging treatments for dry age-related macular degeneration (AMD) focus on two main strategies: preventing cell loss through neuroprotection and oxidative damage prevention, and suppressing inflammation.

Current and potential therapies include neuroprotective drugs, micronutrient supplementation, visual cycle modulators, and anti-inflammatory agents, suggesting a combination approach may be most effective in managing AMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New approaches and potential treatments for dry age-related macular degeneration. Damico, FM., Gasparin, F., Scolari, MR., et al.[2022]

In a study of 10 patients with chronic graft-versus-host disease (cGVHD), long-term use of 3% diquafosol ophthalmic solution significantly improved symptoms of dry eye disease, particularly corneal and conjunctival health, without major adverse events.

After an average treatment duration of 12 months, diquafosol improved tear film stability and reduced staining scores, indicating its efficacy in managing dry eye symptoms associated with cGVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Topical Diquafosol Tetrasodium Treatment of Dry Eye Disease Caused by Chronic Graft-Versus-Host Disease: A Retrospective Study. Yamane, M., Ogawa, Y., Fukui, M., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Antibacterial activity of disulfiram and its metabolites. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? [2015]

3. England pubmed.ncbi.nlm.nih.gov

How to get the best out of antabuse. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Lack of immunomodulating effect of disulfiram on HIV positive patients. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of antabuse (disulfiram) on Rous sarcoma virus and on eukaryotic cells. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Repurposing Drugs for Treatment of Age-Related Macular Degeneration. [2023]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Treatment with the peptide bioregulator retinalamine in patients with tuberculosis of the organ of vision]. [2008]

9. Brazil pubmed.ncbi.nlm.nih.gov

New approaches and potential treatments for dry age-related macular degeneration. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Long-Term Topical Diquafosol Tetrasodium Treatment of Dry Eye Disease Caused by Chronic Graft-Versus-Host Disease: A Retrospective Study. [2018]