Gene Therapy for Leber's Optic Atrophy

(LHON Trial)

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Byron Lam

Disqualifiers: Pregnancy, Optic disc drusen, Diabetes, Neurodegenerative, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Single administration

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new gene therapy, scAAV2-P1ND4v2, for individuals with Leber's Hereditary Optic Neuropathy (LHON), a condition that causes vision loss. The therapy uses a special viral vector to deliver a gene that helps mitochondria in eye cells function properly. Researchers are testing different doses to determine the safest and most effective one. Individuals with LHON who have the G11778A genetic mutation and experience severe vision loss in one or both eyes may be suitable candidates for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, researchers found that the gene therapy treatment scAAV2-P1ND4v2 was generally well-tolerated. Most participants experienced only mild side effects, easily managed with standard eye treatments. Other research has shown that the treatment helps protect vision without causing major problems. While scAAV2-P1ND4v2 remains under study, early findings are promising for its safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Leber's Optic Atrophy?

Researchers are excited about scAAV2-P1ND4v2 for Leber's Optic Atrophy because it uses gene therapy to address the genetic root of the condition. Unlike current treatments that focus mainly on managing symptoms, this therapy introduces a modified virus to deliver a healthy copy of the ND4 gene directly into retinal cells, potentially halting or even reversing vision loss. This targeted approach could offer more lasting improvements in vision compared to existing options, which don't address the underlying genetic cause. Additionally, the therapy is being tested across various doses to find the most effective and safe option for different stages of vision loss.

What evidence suggests that this gene therapy might be an effective treatment for Leber's Optic Atrophy?

Research has shown that scAAV2-P1ND4v2, a type of gene therapy, is being tested to treat Leber's Hereditary Optic Neuropathy (LHON), a condition that causes vision loss. The trial includes various treatment arms with different dosages of scAAV2-P1ND4v2 to evaluate its effectiveness and safety. This therapy replaces a faulty gene linked to this vision problem. Studies in animals, such as rodents and primates, have demonstrated the treatment's safety. Early results also suggest it might help prevent further vision loss. While these findings are encouraging, more research is needed to confirm its effectiveness in people. ^{3 6 7 8 9}

Who Is on the Research Team?

Byron Lam, MD

Principal Investigator

Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136

Are You a Good Fit for This Trial?

This trial is for individuals aged 15 or older with Leber's Hereditary Optic Neuropathy (LHON) and a specific genetic mutation (G11778A). Participants must be in good health, able to perform visual tests, comply with study procedures, and provide informed consent. Exclusions include other eye diseases, severe liver issues, blood disorders, previous eye surgery on the affected eye, pregnancy/nursing women not using contraception, certain systemic or autoimmune diseases.

Inclusion Criteria

Able and willing to provide informed consent before undergoing any study related procedures

I am 15 years old or older.

Good general health as based on the investigator's assessment of the history, physical examination and laboratory testing performed at the baseline examination

Exclusion Criteria

Unable or unlikely to return for scheduled protocol visits

Your liver enzymes or bilirubin levels are too high, or your red blood cell, white blood cell, or platelet counts are too low.

Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravitreal injection of scAAV2-P1ND4v2 at varying doses to assess safety and tolerability

Single administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including ocular and systemic toxicity assessments

36 months

What Are the Treatments Tested in This Trial?

Interventions

• scAAV2-P1ND4v2

Trial Overview The trial is testing different doses of an injection called scAAV2-P1ND4v2 to treat LHON. There are four dose levels: low, medium-higher and high. The main goal is to check if these injections are safe and do not cause any loss of vision in the treated eyes.

How Is the Trial Designed?

Group I: Medium dose (5.81x10e9 vg) Experimental Treatment 1 Intervention

Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg.

Group II: Low-dose (1.18x10e9 vg) Experimental Treatment 1 Intervention

Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg

Group III: Higher dose (1x10e11vg) Experimental Treatment 1 Intervention

Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg.

Group IV: High dose (2.40x10e10 vg) Experimental Treatment 1 Intervention

Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg.

Who Is Running the Clinical Trial?

Byron Lam

Lead Sponsor

Trials

2

Recruited

30+

National Eye Institute (NEI)

Collaborator

Trials

572

Recruited

1,320,000+

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02161380

NCT02161380 | Safety Study of an Adeno-associated Virus ... The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4249950/

LHON Gene Therapy Vector Prevents Visual Loss and Optic ... Discussion. Our results here demonstrated that intravitreal injection of ScAAV2-P1ND4v2 was well tolerated in normal rodents and nonhuman primates and in a ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0039625724001309

Meta-analysis of treatment outcomes for patients with m. ... Our aim was to assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT-ND4 mutation who had no ...

4. clinicaltrial.be clinicaltrial.be/en/details/11797?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Safety Study of an Adeno-associated Virus Vector for Gene... The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene ...

5. jamanetwork.com jamanetwork.com/journals/jamaophthalmology/fullarticle/1814538

Safety and Effects of the Vector for the Leber Hereditary ... Koilkonda et al demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial for Leber ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02161380

NCT02161380 | Safety Study of an Adeno-associated Virus ... The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy in ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4266107/

Safety and Effects of the Vector for the Leber Hereditary ... These findings indicate that WT allotopic ND4 gene therapy prevents visual loss and RGC dysfunction with gene delivery using the highly efficient expression ...

8. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT02161380

Gene Therapy Trial Report Safety Study of an Adeno-associated Virus Vector for Gene Therapy of Leber's Hereditary Optic Neuropathy ; Compound Name, ScAAV2-P1ND4v2 ; Sponsor, Byron Lam.

9. ajo.com ajo.com/article/S0002-9394(22)00464-0/fulltext

Safety of Lenadogene Nolparvovec Gene Therapy Over 5 ... The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments. Keywords. Leber hereditary optic ...