Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients

Study Overview
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Brief Summary
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This trail is meant to evaluate the safety and efficacy of ZM-01 of X-linked retinoschisis. Unilateral intravitreal injections (IVT) will be given into the subject's Study Eye.

Detailed Description
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X-linked retinoschisis (XLRS) is a rare, inherited retinal disease caused by mutations in the RS1 gene. Individuals affected by XLRS often experience progressive visual impairment from a young age, potentially leading to legal blindness. There is currently no established clinical treatment available. We developed a innovative adeno-associated virus (AAV)-based gene therapy for individuals with XLRS. Six to nine subjects with XLRS were received a single unilateral intravitreal injection of ZM-01 at ascending doses.

Official Title
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Prospective, Dose-Escalating, Investigator Initiated Trial to Evaluate the Safety and Efficacy of ZM-01 in 3-18 Year-old Male Subjects With X-linked Retinoschisis

Conditions
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X-linked Retinoschisis

Intervention / Treatment
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* Drug: ZM-01-L
* Drug: ZM-01-H


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who meet all of the following criteria will be enrolled into the study Diagnosis of X-linked retinoschisis consistent with the presence of RS1 gene mutation Male, aged between 3 and 18 years old, in overall good health except for XLRS condition Capable of undergoing visual and retinal function assessment. The visual acuity of the study eye not better than: 0.4 (68 ETDRS letters equivalent) No carbonic anhydrase inhibitors have been used at present and for 3 months before treatment Laboratory tests meet the following criteria: Hemoglobin ≥ 11.0 g/dL White blood cell counts ranged from 3,300 to 12,000 cells /mm³; Platelet count 125,000-550,000 /mm³; Alanine aminotransferase (ALT) is not higher than 1.5 times the upper limit of the normal range of laboratory tests; Serum creatinine was no higher than 1.1 times the upper limit of the normal range for laboratory tests; Prothrombin time (PT) ≤14.5 seconds and partial thromboplastin time (PTT) ≤ 36.0 seconds. Willing to discontinue aspirin, aspirin-containing products, and any other medications that may alter clotting function at least 7 days before dosing. Be able to understand and sign informed consent. Exclusion Criteria: Subjects who meet any of the following exclusion criteria before enrollment were excluded from the study Previously received any AAV gene therapy The following mutations in RS1 gene: R141H, C59S or C223S Pre-existing eye conditions that cause severe vision loss or increase the risk of intravitreal injections (e.g., advanced glaucoma, uveitis, or severe retinal detachment) Ocular diseases in which there is opacity of the lens, cornea, or other media, hindering adequate observation and examination of the retina Use anticoagulant or antiplatelet drugs within 7 days before dosing Use any experimental drug within 3 months prior to registration Presented any situation that causes the investigator to believe the subject might not adhere to the study protocol or that participation might pose an unacceptable risk to the subject

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: group 1<br>IVT administration of a single low dose ZM-01 injection | Drug: ZM-01-L<br>* rAAV-hRS1 intravitreal injection of low dose<br>* Other names: rAAV-hRS1;|
| Experimental: group 2<br>IVT administration of a single high dose ZM-01 injection | Drug: ZM-01-H<br>* rAAV-hRS1 intravitreal injection of high dose<br>* Other names: rAAV-hRS1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and serious adverse events | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event will not need to have a causal relationship with the treatment. A serious adverse event (SAE) is any untoward medical occurrence at any dose that leading to the following: Results in death; Life-threatening, refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe; Significant or permanent disability/incapacity, where disability refers to a serious disruption and damage of a person's ability to perform normal life functions; Requires inpatient hospitalization or prolongation of existing hospitalization; Congenital anomaly or birth defect; Other medically important events. | baseline to day 7, month 1, 2 | 
| Change in best corrected visual acuity (BCVA) | BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling E chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study. | baseline to day 7, month 1, 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and serious adverse events | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event will not need to have a causal relationship with the treatment. A serious adverse event (SAE) is any untoward medical occurrence at any dose that leading to the following: Results in death; Life-threatening, refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe; Significant or permanent disability/incapacity, where disability refers to a serious disruption and damage of a person's ability to perform normal life functions; Requires inpatient hospitalization or prolongation of existing hospitalization; Congenital anomaly or birth defect; Other medically important events. | baseline to month 3, 4, 6, 9, 12 | 
| Change in Quality of Life | Quality of Life will be measured using Pediatric Eye Questionnaire (PedEyeQ) or other similar questionnaires before and after treatment | baseline to month 9, 12 | 
| Change in best corrected visual acuity (BCVA) | BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart or tumbling E chart. This approach was chosen to facilitate visual acuity testing in children who cannot recognize letters, which was more appropriate for this study. | baseline to month 3, 4, 6, 9, 12 | 
| Change in visual field | Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed. | baseline to month 1, 2, 3, 4, 6, 9, 12 | 
| Change in electrophysiology result | The ERG measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV). | baseline to month 1, 2, 3, 4, 6, 9, 12 | 
| Anti-AAV neutralizing antibody titer, Anti-RS1 neutralizing antibody titer | Peripheral blood samples were collected from each subjects to measure the AAV8 antibody levels and virus titers in the peripheral blood. | baseline to day 1, 7 and month 1, 2 | 
| Change in the retina cavity assessed by macular OCT | Optical coherence tomography (OCT) of the macula was performed in both eyes of each participant at each visit. | baseline to day 7, month 1, 2, 3, 4, 6, 9, 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, AAV, RS1