CRISPR/Cas9 Instantaneous Gene Editing Therapy to Intraocular Hypertensive POAG With MYOC Mutation

A Clinical Study on CRISPR/Cas9 Instantaneous Gene Editing Therapy to Primary Open-angle Glaucoma With Elevated Intraocular Pressure and MYOC Gene Mutation

This study is intented to evaluate the safety, tolerability and preliminary efficacy of CRISPR/Cas9 Instantaneous Gene Editing Therapy (BD113 virus-like particle, also BD113vLVP) in patients with primary open-angle glaucoma (POAG) with elevated intraocular pressure and MYOC gene mutation. The main objectives to evaluate the safety and tolerability BD113vLVP) in POAG patients with intraocular hypertension and MYOC mutation, and secondary objectives is to explore the preliminary efficacy and the metabolism characteristics of BD113vLVP in participants.

Study Overview

• Status: Recruiting
• Conditions: Primary Open Angle Glaucoma
• Intervention / Treatment: Genetic: BD113vVLP

Detailed Description

This is an open, single-dose, two-arm, non-randomised clinical study. A total of 6 to 9 POAG patients with high intraocular pressure were enrolled and divided into two test groups. Test Group 1 recruits 3 POAG patients, who have elevated IOP and positive or negative MYOC mutation and target interventing eye is no vision. Test Group 2 will recruit 3 to 6 POAG patients with MYOC mutations and visual acuity. In order to better verify the lowering IOP effectiveness of BD113vVLP, another 2 or 3 participants will be recruied in Group 2 on-demand. Each participant will receive single dosing BD113vVLP (4µg p24) by intracameral injection in the interventing eye, then conduct the evaluations of the safety and efficacy according to visit schedule in 1 year follow-up。

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fujun Li, M.D.; Phone Number: 086-191 2131 1061; Email: fujun.li@bdgene.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Recruiting
      • Beijing tongren Hospital, Capital Medical University
      • Contact: Yufei Teng, M.D.; Phone Number: 086-185 1077 8021; Email: tengyufei2001@163.com
      • Principal Investigator: Ningli Wang, M.D.
      • Sub-Investigator: Yufei Teng, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed ICF;
2. Aged 18 to 65 years old;
3. Primary open Angle glaucoma (POAG) with elevated intraocular pressure (IOP) was diagnosed with ≥1 year medical history record ;
4. Good function level of organs;
5. Good compliance and willing to comply with the visit schedule, laboratory tests and other specified test etc. per protocol;
6. Agreeing to accept a long-term safety follow-up after 1 year of study.

Special Inclusion Criteria for Group 1:

• Target intervenning eye is no visual acuity;
• The intraocular pressure (IOP) was ≤35 mmHg and > 21 mmHg after receiving a combination therapy of 2 or more drugs lowering IOP.

Special Inclusion Criteria for Group 2:

• MYOC gene mutation was detected in peripheral blood nucleated cells ;
• The intraocular pressure (IOP) was ≤30 mmHg and > 21 mmHg after receiving a combination therapy of 2 or more drugs lowering IOP;
• Both eyes have a Shaffer Angle mirror rating greater than 3.

Exclusion Criteria:

1. Secondary glaucoma;
2. Any active or recurrent intraocular infection or inflammation, including but not limited to uveitis;
3. The target intervenning eye has severe xerophthalmia or clinically significant active corneal disease;
4. Any condition no accepting the measure of IOP;
5. Any positive of human immunodeficiency virus type 1/2 (HIV-1/HIV-2) antibody, treponema pallidum (TP) specific antibody, human T-lymphotropic virus type 1 or 2 (HTLV-1/HTLV-2) antibody, or vesicular stomatitis virus G (VSV-G) antibody;
6. Any of hepatitis B virus (HBV) HbsAg or HBV-DNA, hepatitis C virus (HCV) HCAb, or epstein-barr virus (EBV), or cytomegalovirus (CMV) nucleic acid test is positive;
7. Severe active bacterial, viral, fungal, malaria or parasitic systemic infection;
8. Any past or present malignancy, myeloproliferative or immunodeficient disease;

9. History of major organ diseases or abnormalities in laboratory tests, including:

   1. Liver cirrhosis, liver fibrosis or active hepatitis, and/or abnormal liver function tests (serum total bilirubin (TBIL) ≥1.5 x upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥2.5×ULN; Alkaline phosphatase ≥2.5 × ULN);
   2. Cardiovascular and cerebrovascular diseases, including uncontrolled hypertension, myocardial infarction, myocarditis, arrhythmia, stroke, etc.;
   3. Kidney disease, or creatinine ≥ 1.5ULN and creatinine clearance < 30% normal level (using the Cockcroft-Gault equation);
   4. Endocrine disorders, such as insulin-dependent diabetes mellitus, hyperthyroidism or hypothyroidism;
   5. Severe pulmonary hypertension, chronic obstructive pulmonary disease, interstitial pneumonia;
10. Any severe psychiatric disorders;
11. Participating in another clinical study of a drug or device, or administrated the investigational drug within 42 days prior to the screening visit;
12. Pregnant or lactating women;
13. Refusing to accept any contraception measures;
14. Allergic to clinical investigational drugs or their excipients;
15. Other conditions assessed by the investigator as unsuitable for participation in this study.

Special Exclusion Criteria for Group 2:

• Retinal diseases: complicated with unexplained quadrant blindness, neovascularization age-related macular degeneration, retinal branch vein obstruction, central retinal vein obstruction, cystoid macular edema, macular hiatal hole and central serous retinopathy;
• A history of anterior chamber angle stenosis, congenital glaucoma, or angle closure, clinically significant anterior peripheral adhesion, or extensive cicatricial adhesion caused by surgery/laser therapy in the anterior chamber angle;
• The central corneal thickness is less than 480 μm or more than 620 μm.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: POAG without vision for interventional eye; Interventional eye of participants with POAG has no vision, with mutated or unmutated MYOC gene. Single dose of BD113vVLP will be administrated intracamerally for target interventional eye.	Genetic: BD113vVLP; CRISPR/Cas9 gene editing technology, called BD113vVLP (also BD113 virus-like particle) which is a developing product of gene therapy from modified third-generation integrated defective lentivirus, can deliver gRNA/Cas9 ribonucleoprotein complex (RNP). It works to knock out or knock down the mutated MYOC gene. The BD113vVLP is administrated by intracamerally injecton (sigle-dose: 4ug/p24) for each target interventional eye.; Other Names: BD113 virus-like particle; CRISPR/Cas9 mRNA instantaneous gene editing technology
Experimental: Group 2: POAG with vision for interventional eye; Interventional eye of participants with POAG has vision acuity, and MYOC gene mutation test is positive. Single dose of BD113vVLP will be administrated intracamerally for target interventional eye.	Genetic: BD113vVLP; CRISPR/Cas9 gene editing technology, called BD113vVLP (also BD113 virus-like particle) which is a developing product of gene therapy from modified third-generation integrated defective lentivirus, can deliver gRNA/Cas9 ribonucleoprotein complex (RNP). It works to knock out or knock down the mutated MYOC gene. The BD113vVLP is administrated by intracamerally injecton (sigle-dose: 4ug/p24) for each target interventional eye.; Other Names: BD113 virus-like particle; CRISPR/Cas9 mRNA instantaneous gene editing technology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ocular adverse events (AEs)	The charactaristics of ocular adverse events include endophthalmitis, hypopyon, hyphaema and corneal injection site reaction etc. will be evaluated at Week 1, Week 2, Week 3, Week 4, Month 6 and Month 12 after BD113vVLP administration.	12 months
Number and percentage of participants whose IOP decrease ≤21 mmHg	at Month 1, Month 2, Month 3, Month 6 and Month 12 after BD113vVLP administration	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic adverse events (AEs): The type, number and incidence of AEs and serious adverse events (SAEs)	Systemic adverse events (AEs): The type, number and incidence of AEs and serious adverse events (SAEs) will be analysized within 12 months after BD113vVLP administration.	12 months
Number and percentage of participants whose IOP decrease by ≥ 20% from baseline	at Month 1, Month 2, Month 3, Month 6 and Month 12 after BD113vVLP administration	12 months
Any ocular maligancies related to BD113vVLP	after BD113vVLP administration	12 months
Changes in BCVA from baseline	at Month 3, Month 6 and Month 12 after BD113 vVLP administration, not applicable to group 1.	12 months
Changes in visual fields from baseline	at Month 3, Month 6 and Month 12 after BD113 vVLP administration, not applicable to group 1.	12 months
Changes in RNFL from baseline	at Month 3, Month 6 and Month 12 after BD113 vVLP administration, not applicable to group 1.	12 months
P24 and Cas9 proteins concentration in aqueous humor	at hour 0 and Month 1 after BD113vVLP administration	1 months
P24 and Cas9 proteins concentration in blood	at hour 0 and Day 7 after BD113vVLP administration	7 days
Blood antibodies of anti-p24 protein and anti-Cas9 proteins	at Month 6 and Month 12 after BD113vVLP administration	12 months

Collaborators and Investigators

• Sponsor: Shanghai BDgene Co., Ltd.
• Collaborators: Beijing Tongren Hospital
• Investigators: Study Director: Yufei Teng, M.D., Beijing Tongren Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: June 13, 2024
• First Submitted That Met QC Criteria: June 13, 2024
• First Posted (Actual): June 20, 2024

Study Record Updates

• Last Update Posted (Actual): June 24, 2024
• Last Update Submitted That Met QC Criteria: June 19, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: POAG; primary open angle glaucoma; elevated intraocular pressure; MYOC gene mutation
• Additional Relevant MeSH Terms: Eye Diseases; Ocular Hypertension; Glaucoma; Glaucoma, Open-Angle
• Other Study ID Numbers: BD-MMG-113001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No