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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, ATSN-201, to determine its safety and tolerability for individuals with X-linked retinoschisis (XLRS), a genetic eye condition affecting vision. Researchers are exploring different doses to identify the optimal delivery method. The trial is open to males diagnosed with XLRS due to RS1 gene mutations and who meet specific vision criteria. Participants should not have undergone recent eye surgery or have other eye conditions that could increase the risk of further vision loss. As a Phase 1 trial, participants will be among the first to receive this treatment, aiding researchers in understanding its effects in humans.

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.

Is there any evidence suggesting that ATSN-201 is likely to be safe for humans?

Research has shown that ATSN-201, a gene therapy for X-linked retinoschisis (XLRS), was safe in previous trials. In these studies, researchers injected ATSN-201 under the retina. The therapy provides a working version of the retinoschisin gene, which individuals with XLRS lack.

Safety data from earlier studies are promising, showing no serious unexpected medical problems up to one year after treatment. Most participants handled the treatment well, experiencing no severe side effects.

The current trial is in its early stages, focusing mainly on assessing safety and treatment tolerance. While early trials aim to ensure safety, positive results from earlier research suggest that ATSN-201 is generally well-tolerated and safe. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ATSN-201 for retinoschisis because it offers a new approach through gene therapy, which targets the underlying genetic cause of the disease rather than just managing symptoms. Unlike standard treatments that focus mostly on symptom relief, ATSN-201 aims to correct the gene responsible for the condition, potentially providing a more long-term solution. This innovative mechanism could lead to significant improvements in vision and quality of life for patients, setting it apart from existing therapies.

What evidence suggests that ATSN-201 might be an effective treatment for X-linked retinoschisis?

Research has shown that ATSN-201, the investigational treatment in this trial, may help treat X-linked retinoschisis (XLRS), a genetic eye condition. In previous studies, patients who received ATSN-201 experienced improvements in their vision, with most seeing positive results without serious side effects. This gene therapy provides a healthy copy of the RS1 gene, which helps maintain the retina, the light-sensitive part of the eye. This process could stop or even reverse vision loss in people with XLRS. Overall, early findings suggest that ATSN-201 could be an effective treatment option for this condition. Participants in this trial will join different cohorts to evaluate various dosages and volumes of ATSN-201. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. atsenatx.com atsenatx.com/press-release/atsena-therapeutics-announces-positive-clinical-data-from-part-a-of-phase-i-ii-trial-evaluating-atsn-201-gene-therapy-to-treat-x-linked-retinoschis/

Atsena Therapeutics Announces Positive Clinical Data ... A Phase I/II clinical trial evaluating subretinal injection of ATSN-201 for the treatment of X-linked retinoschisis (XLRS).

2. atsenatx.com atsenatx.com/press-release/atsena-therapeutics-announces-dosing-complete-in-adults-in-part-b-of-the-phase-i-ii-iii-lighthouse-trial-evaluating-atsn-201-to-treat-x-linked-retinoschisis/

Atsena Therapeutics Announces Dosing Complete for ... ATSN-201 is the first XLRS gene therapy to demonstrate efficacy and positive safety data in a Phase I/II trial, with the majority of patients ...

3. healio.com healio.com/news/ophthalmology/20250522/gene-therapy-for-xlinked-retinoschisis-promising-in-phase-12-trial

Gene therapy for X-linked retinoschisis promising in phase ... A subretinal injection of ATSN-201 gene therapy demonstrated promising results in patients with X-linked retinoschisis in a phase 1/2 clinical trial.

4. cgtlive.com cgtlive.com/view/fda-supports-pivotal-trial-expansion-atsn-201-gene-therapy-xlrs

FDA Supports Pivotal Trial Expansion of ATSN-201 Gene ... The therapy has shown a favorable safety profile up to 1 year post treatment, with no serious adverse events reported.The LIGHTHOUSE trial is ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02416622

NCT02416622 | Safety and Efficacy of rAAV-hRS1 in ... This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing retinoschisin (rAAV2tYF-CB-hRS1) in patients with X- ...

6. atsenatx.com atsenatx.com/wp-content/uploads/2024/10/AAO_Oct2024.pdf

Interim Safety and Efficacy of ATSN-201 Dose Escalation ... ATSN-201 subretinal gene therapy. • Introduces the functional human retinoschisin (hRS1) gene. • Human rhodopsin kinase promoter targets ...

7. retinaldegenerationfund.org retinaldegenerationfund.org/news/news-posts/atsena-therapeutics-announces-dosing-complete-for-adults-in-part-b-of-the-phase-i-ii-iii-lighthouse-trial-evaluating-atsn-201-to-treat-x-linked-retinoschisis/

Atsena Therapeutics Announces Dosing Complete for ... ATSN-201 is the first XLRS gene therapy to demonstrate efficacy and positive safety data in a Phase I/II trial, with the majority of ...