Safety and Tolerability Study of Gene Editing Drug ZVS203e in Participants With Retinitis Pigmentosa

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of ZVS203e administered via subretinal injection in participants with RP caused by RHO site-specific gene mutation (RHO-RP).

Detailed Description
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This is a single-arm, open-label, single ascending dose study of ZVS203e in participants with RHO-RP. Up to 9 participants will be enrolled in this study. Safety, efficacy and vector shedding characteristics of ZVS203e are then measured.

Official Title
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A Single-arm, Open-label Exploratory Clinical Study to Assess the Preliminary Safety of the Gene Editing Drug ZVS203e for the Management of Retinitis Pigmentosa Caused by Mutations in the RHO Gene

Conditions
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Retinitis Pigmentosa

Intervention / Treatment
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* Drug: ZVS203e


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients with clinical diagnosis of Retinitis Pigmentosa (RP) (age ≥ 18 years) ; 2. Genetic test confirmed to carry a fix mutation of RHO and carry no pathogenic mutations of other ophthalmic genetic diseases; 3. Meet the following target eye selection criteria： Best corrected visual acuity between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR, equivalent to Snellen visual acuity of hand move to 20/63) ; 4. Agree to take effective contraceptive measures from the beginning of the study to 1 year after the administration; 5.Willingness to adhere to protocol as evidenced by written informed consent; Exclusion Criteria: 1. Existing or pre-existing of macular lesions such as retinoschisis or macular membrane, or other eye conditions interfering with the surgery or the interpretation of the clinical endpoint, in the investigators' opinion; 2. The study eye has been treated with other drugs within 3 months that could affect the evaluation of the investigational drug; 3. The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy; 4. The presence of an ocular/visual disease, disorder or lesion known to cause, or to be associated with, vision loss, or whose associated treatment or therapy is known to cause, or to be associated with, vision loss； 5. Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen; 6. Known allergy to the drug planned for use in the study； 7.Those with the following laboratory abnormalities which are clinically significant: Liver function: chronic liver disease, ALT increased >2 times the upper limit of normal; With uncontrolled hypertension, mean systolic blood pressure ≥ 160 mmHg or mean diastolic blood pressure ≥ 100 mmHg; With uncontrolled diabetes, HbA1c>10%; Patients with abnormal coagulation function (prothrombin time ≥ upper limit of normal (3 seconds' longer), activated partial thromboplastin time ≥ upper limit of normal (10 seconds' longer)); Serum virology test: Active hepatitis B, hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab) or syphilis antibody positive; 8. Having any past or present medical history that may affect the safety of the trial or the in vivo process of the drug, especially the medical history of cardiovascular, hepatic, renal, endocrine, gastrointestinal, pulmonary, neurological, hematological, oncologic, immunological or metabolic disorders and others that are thought clinically significant by the investigator； 9. Participation in any medicine or medical device clinical trials within 3 months prior to enrollment; 10. Neutralizing antibodies to rAAV> 1:1000 by immunologic test; 11. For females in pregnancy or lactation period; 12. Any other conditions which leads the investigator to determine the participant is unsuitable for this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Three cohorts of 3 patients each. All the patients enrolled in the study will receive a single subretinal injection in one eye. Cohort 1: Subretinal administration of a single low dose ZVS203e at Day 0. Cohort 2: Subretinal administration of a single medium dose ZVS203e at Day 0. Cohort 3: Subretinal administration of a single high dose ZVS203e at Day 0. | Drug: ZVS203e<br>* ZVS203e is a rAAV-mediated gene editing drug that silences RHO mutant protein expression by CRISPR/Cas9 editing system.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs） | 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. | Baseline up to Week 52 | 
| Incidence of serious adverse events (SAEs) | 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 up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in BCVA after ZVS203e treatment | BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart. | Baseline up to Week 52 | 
| Change from Baseline in visual field | Visual field will be assessed by Humphrey perimetry, changes in VFI, MD, PSD will be analyzed. | Baseline up to Week 52 | 
| Change from Baseline in contrast sensitivity | Change from baseline in contrast sensitivity will be measured using the CSV-1000E instrument. | Baseline up to Week 52 | 
| Change from Baseline in multi-luminance mobility test (MLMT) | MLMT was assessed at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night). The score range is between -1 (the worst) and 6 (the best). | Baseline up to Week 52 | 
| Change from Baseline in retinal thickness | Retinal thickness will be assessed for both eyes using OCT. | Baseline up to Week 52 | 
| Change from Baseline in fundus autofluorescence (FAF) | FAF is a noninvasive test to explore the health and metabolic status of retinal pigment epithelial cell/photoreceptor complex. | Baseline up to Week 52 | 
| Change from Baseline in color vision | Subjects' color vision was classified and graded by Farnsworth Munsell 100 hue. | Baseline up to Week 52 | 
| Change from Baseline in mfERG | The measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV). | Baseline up to Week 52 | 
| Change from Baseline in NEI VFQ-25 total score | National eye institute 25-item visual function questionnaire (NEI VFQ-25) consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. | Baseline up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene editing, retinitis pigmentosa, RHO, rAAV