Clinical trial NCT04722107: Safety Study of rAAV2/8-hCYP4V2 in Patients With Bietti's Crystalline Dystrophy (BCD)
Official title: Safety Trial of rAAV2/8-hCYP4V2 Gene Replacement Therapy Drug Administered as a Single Subretinal Injection in Patients With Bietti's Crystalline Dystrophy (BCD)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: EARLY_PHASE1
Conditions: Bietti's Crystalline Dystrophy
Lead sponsor: Beijing Tongren Hospital
Sponsor class: OTHER
First posted: 2021-01-25
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Primary Objectives: To evaluate the safety of rAAV2/8-hCYP4V2 gene replacement therapy drug administered as a single subretinal injection in patients with Bietti's Crystalline Dystrophy (BCD).

Secondary Objectives: To preliminarily explore the clinical effectiveness of rAAV2/8-hCYP4V2 gene replacement therapy drugs.

Detailed description: This is a single-arm, open-label, and single-center study of ZVS101e in patients with BCD. A total of 12 participants will be enrolled. A retinal surgeon will administer the vector by subretinal injection. Safety, efficacy and vector shedding characteristics of ZVS101e are then measured over 2 years.

Eligibility criteria: Inclusion Criteria:

* 1) Age ≥ 18 years old at the time of informed consent ;
* 2) Patients with a clinical diagnosis of Bietti's crystalline dystrophy (BCD);
* 3) Genetic test confirmed to carry two pathogenic variants of CYP4V2;
* 4) 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); No refractive media clouding affecting fundus examination, visual examination and retinal function examination; The eye with the poorer visual acuity of the two eyes of the subject is the target eye. Note: For all subjects, only one eye will be used as the "target eye". If both eyes meet the inclusion criteria and the visual acuity is comparable, the target eye will be determined medically by the investigator.
* 5) Agree to take effective contraceptive measures from the beginning of the study to 2 year after the administration;
* 6) Voluntarily participate in this clinical trial and have signed the informed consent form.

Exclusion Criteria:

* 1) Patients lack sufficient retinal photoreceptors, retinal photoreceptors less than 1 optic disc area or retinal thickness less than 100 μm in the macula；
* 2) Existing or pre-existing of choroidal neovascular (CNV) lesions that were secondary to BCD, or other eye conditions interfering（ (e.g., high refractive error, retinal vasculitis, etc.) ） that may prevent surgery or interfere with the interpretation of the study endpoint;
* 3) Prior use of medicines which may affect the experimental observation within the 6 months before screening (such as ranibizumab, bevacizumab, aflibercept, conbercept)；
* 4) Prior intraocular surgery in the target eye (e.g. PDT, pars plana vitrectomy, retinal laser therapy )
* 5) Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen；
* 6) Allergic constitution (such as those who are allergic to two or more drugs and foods);
* 7) Abnormal physical examination, vital signs, laboratory tests (blood routine, urine routine, blood biochemistry, coagulation function, immunological examination, female blood pregnancy), 12-lead ECG, X-ray chest radiograph findings with any clinically significant abnormality, and where participation in this study may increase the subject's risk or interfere with data interpretation as assessed by the investigator；
* 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)Carrying other ophthalmic pathogenic mutations
* 13) Any other conditions which leads the investigator to determine the participant is unsuitable for this study.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: 24 months
measure: Incidence of serious adverse events
timeFrame: 24 months
measure: Clinically important changes from baseline after ZVS101e treatment
timeFrame: 24 months
Secondary outcomes:
measure: Mean change from baseline in BCVA after ZVS101e treatment
timeFrame: 24 months
measure: Change from Baseline in visual field
timeFrame: 24 months
measure: Change from Baseline in contrast sensitivity
timeFrame: 24 months
measure: Change from Baseline in multi-luminance mobility test (MLMT)
timeFrame: 24 months
measure: Change from Baseline in OCTA
timeFrame: 24 months
measure: Change from Baseline in microperimetry
timeFrame: 24 months
measure: Change from Baseline in mfERG
timeFrame: 24 months
measure: Change from Baseline in retinal thickness
timeFrame: 24 months
measure: Change from Baseline in NEI VFQ-25 total score
timeFrame: 24 months
measure: Change from Baseline in fundus autofluorescence (FAF)
timeFrame: 24 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tongren Hospital
state: Beijing
Study officials:
affiliation: Vice President of Beijing Tongren Hospital
name: wenbin Wei, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jia R, Meng X, Chen S, Zhang F, Du J, Liu X, Yang L. AAV-mediated gene-replacement therapy restores viability of BCD patient iPSC derived RPE cells and vision of Cyp4v3 knockout mice. Hum Mol Genet. 2023 Jan 1;32(1):122-138. doi: 10.1093/hmg/ddac181.