Gene Therapy for Retinoschisis

(LIGHTHOUSE Trial)

Recruiting at 3 trial locations

Overseen By Atsena Therapeutics Clinical Trials

Age: Any Age

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Atsena Therapeutics Inc.

Disqualifiers: Pre-existing eye conditions, prior ocular gene therapy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will test the safety of ATSN-201, a one-time eye injection, in males aged 6 and older with a specific eye condition called XLRS.

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 trial coordinators or your doctor.

What data supports the effectiveness of the treatment ATSN-201 for retinoschisis?

Research shows that gene therapy using AAV vectors can improve retinal function and structure in mouse models of retinoschisis, suggesting that similar treatments might help in human cases. These studies found that delivering the retinoschisin gene to the retina can restore normal retinal signaling and reduce retinal damage. ^{1 2 3 4 5}

Is gene therapy for retinoschisis safe for humans?

Gene therapy for retinoschisis has been generally well tolerated in human trials, with some participants experiencing dose-related eye inflammation that resolved with medication. No serious safety concerns have been reported, and the treatment is being further explored to ensure its safety and effectiveness. ^{1 3 5 6 7}

How is the treatment ATSN-201 unique for retinoschisis?

ATSN-201 is a gene therapy that uses a virus to deliver the retinoschisin gene directly into the eye, which helps restore normal function in the retina. Unlike other treatments, it is administered through a simple injection into the vitreous (the gel-like substance inside the eye), making it less invasive than traditional methods that require surgery. ^{1 2 3 5 7}

Eligibility Criteria

This trial is for male patients with X-linked retinoschisis (XLRS) due to RS1 mutations. Adults must be between 18 and 64 years old, while children should be aged 6 to under 18. Participants need a specific level of vision clarity. Those who've had previous eye gene therapy or certain eye conditions/surgeries are excluded.

Inclusion Criteria

I am at least 18 years old for Cohorts 1-3, or between 6 and 17 years old for Cohort 4.

Best corrected visual acuity (BCVA) in study eye of 34 to 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (corresponding to a Snellen acuity of 20/200 to 20/40)

I am a male diagnosed with XLRS due to RS1 gene mutations.

Exclusion Criteria

Treatment in a prior ocular gene or cell therapy study

I haven't had eye surgery or laser treatment in the past 6 months and don't plan any in the next year.

I have an eye condition that could worsen with certain eye injections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time subretinal injection of ATSN-201 in one eye

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Long-term follow-up

Safety and tolerability are evaluated for 5 years

5 years

Treatment Details

Interventions

• ATSN-201

Trial Overview The study tests the safety and effects of ATSN-201, a gene therapy for males with XLRS. It will involve different age groups (cohorts) to assess how well they tolerate this potential new treatment.

Participant Groups

Group I: Cohort 5, Pediatric Experimental Treatment 1 Intervention

ATSN-201 at High Volume

Group II: Cohort 4, Low Volume Experimental Treatment 1 Intervention

Group III: Cohort 4, High Volume Experimental Treatment 1 Intervention

Group IV: Cohort 3, Mid Dose Experimental Treatment 1 Intervention

Group V: Cohort 2, High Dose Experimental Treatment 1 Intervention

Group VI: Cohort 1, Low Dose Experimental Treatment 1 Intervention

Group VII: Cohort 4, Control Active Control 1 Intervention

Who Is Running the Clinical Trial?

Atsena Therapeutics Inc.

Lead Sponsor

Trials

2

Recruited

40+

Findings from Research

AAV vectors can be effectively delivered to all layers of the retina in a mouse model of X-linked juvenile retinoschisis (XLRS) through a simple vitreous injection, avoiding the need for more invasive procedures.

Treatment with these vectors led to significant improvements, including reduced retinal schisis cavities and enhanced retinal signaling, as measured by electroretinogram recordings 11-15 weeks post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Park, TK., Wu, Z., Kjellstrom, S., et al.[2022]

The Rs1h-KO mouse model effectively mimics the structural and functional characteristics of human X-linked juvenile retinoschisis (XLRS), showing significant retinal layer disorganization and an electronegative electroretinogram (ERG) response, which is typical of the disease.

Gene therapy using AAV(2/2)-CMV-Rs1h to deliver the retinoschisin protein successfully restored normal ERG waveforms in the Rs1h-KO mice, demonstrating that this approach can reverse the functional deficits associated with XLRS even after development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with Reversal of the Electronegative Waveform of X-Linked Retinoschisis. Zeng, Y., Takada, Y., Kjellstrom, S., et al.[2022]

AAV5-mediated gene therapy shows significant functional improvement in retinoschisin-deficient mice when administered at various stages of advanced X-linked juvenile retinoschisis, particularly at 15 days, 1 month, and 2 months after birth.

Even when treatment is delayed until 7 months after birth, which corresponds to advanced disease, there are still positive effects on photoreceptor survival and retinoschisin expression, suggesting that human patients with XLRS may also benefit from gene therapy even in later stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse. Janssen, A., Min, SH., Molday, LL., et al.[2022]

Genetically modified mesenchymal stem cells (MSCs) that secrete RS1 protein were successfully injected into the eyes of Rs1h knockout mice, leading to significant reductions in schisis cavity areas (up to 83%) and improved retinal structure and function over 4 months.

This ex vivo gene therapy approach not only reversed structural deficits but also enhanced retinal function, suggesting potential for treating other inherited retinal degenerations caused by extracellular matrix protein deficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An ex vivo gene therapy approach in X-linked retinoschisis. Bashar, AE., Metcalfe, AL., Viringipurampeer, IA., et al.[2018]

In a mouse model of X-linked juvenile retinoschisis, delivering human RS1 cDNA using a specific AAV5-opsin promoter vector successfully restored retinoschisin expression in retinal cells, mimicking normal conditions seen in wild-type mice.

This gene therapy approach resulted in significant improvements in retinal function and structure, preserving photoreceptor cells that would otherwise degenerate, marking a promising advancement in potential treatments for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Min, SH., Molday, LL., Seeliger, MW., et al.[2022]

The AAV8-RS1 gene therapy was generally well tolerated in a phase I/IIa trial involving nine participants with X-linked retinoschisis, with only one individual experiencing significant adverse effects, which were manageable with corticosteroids.

Some participants showed transient closure of retinal cavities, suggesting potential efficacy, but further studies with additional doses and immunosuppressive treatments are needed to fully assess safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Cukras, C., Wiley, HE., Jeffrey, BG., et al.[2022]

The gene therapy rAAV2tYF-CB-hRS1 was found to be generally safe for treating X-linked retinoschisis in a study involving 27 participants (22 adults and 5 children), with no serious adverse events leading to early termination, although some mild to moderate ocular inflammation was observed.

Despite its safety, the treatment did not show significant improvements in visual acuity or other measures of eye function compared to the untreated eye, indicating that while the therapy is well tolerated, it may not be effective in producing measurable benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results. Pennesi, ME., Yang, P., Birch, DG., et al.[2023]

References

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

Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. [2022]

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

RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with Reversal of the Electronegative Waveform of X-Linked Retinoschisis. [2022]

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

Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse. [2022]

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

An ex vivo gene therapy approach in X-linked retinoschisis. [2018]

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

Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. [2022]

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

Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. [2022]

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

Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results. [2023]