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

Primary Open Angle Glaucoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06465537
• Other study ID #: BD-MMG-113001
• Status: Recruiting
• Phase: N/A
• Start date: June 10, 2024
• Est. completion date: December 2025

Study information

• Verified date: June 2024
• Source: Shanghai BDgene Co., Ltd.
• Contact: Fujun Li, M.D.
• Phone: 086-191 2131 1061
• Email: fujun.li[@]bdgene.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be intented to evaluate the safety and tolerability 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 preliminary metabolism characteristics of BD113vLVP in participants.

Description:

This is an open, single-dose, single-arm, single-center clinical study. A total of 6 to 9 patients with primary open Angle glaucoma (POAG) with high intraocular pressure were enrolled and divided into two test groups. Test Group 1 recruits 3 patients with positive or negative MYOC gene mutation POAG and target interventing eye is no vision (absolute stage), and test Group 2 recruit 3 to 6 patients with MYOC mutations and visual POAG. 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 one dosing BD113vVLP (4µg p24) by intracameral injection in the target eye, then undertakes the safety and efficacy evaluations according to visit planning in 1 year follow-up。

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 9
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Signed ICF;

2. Aged 18 to 65 years old, male or female;

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 be willing to comply with the visit schedule, laboratory tests and other specified test etc. per protocol;

6. Agree to accept a long-term safety follow-up after 1 year of study.

Special Inclusion Criteria for Group 1:

• Target eye is no visual;

• 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;

• 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 eye has severe dry eye or clinically significant active corneal disease;

4. Any condition not accepting the determination 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 (measured or calculated 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. Suffering from a severe psychiatric disorders;

11. Participating in another clinical study of a drug or device, or has received 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 clinical 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 in the anterior chamber angle;

• The central corneal thickness is less than 480 µm or more than 620 µm.

Related Conditions & MeSH terms

• Glaucoma
• Glaucoma, Open-Angle
• Primary Open Angle Glaucoma

Intervention

Genetic:
• CRISPR/Cas9 mRNA instantaneous gene editing technology
CRISPR/Cas9 gene editing technology (BD113vVLP) is used to knock out the mutated MYOC gene. The BD113 virus-like particle (vVLP), modified from the third-generation integrated defective lentivirus, is used to deliver gRNA/Cas9 ribonucleoprotein complex (RNP). Single dosing with 4ug/p24 by intracamerally injecton for each target interventional eye.

Locations

Country	Name	City	State
China	Beijing Tongren Hospital, Capital Medical University	Beijing	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Shanghai BDgene Co., Ltd.	Beijing Tongren Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ocular adverse events: Endophthalmitis, hypopyon, hyphaema and corneal injection site reaction etc.	at W1, W2, W3, W4, M6 and M12 after BD113vVLP administration	12 months
Primary	Number and percentage of participants whose intraocular pressure decrease =21 mmHg	at M1, M2, M3, M6 and M12 after BD113vVLP administration	12 months
Secondary	Systemic adverse events (AEs): The type, number and incidence of AEs and serious adverse events (SAEs)	within 12 months after BD113vVLP administration	12 months
Secondary	Number and percentage of participants whose IOP decrease by = 20% from baseline	at M1, M2, M3, M6 and M12 after BD113vVLP administration	12 months
Secondary	BD113vVLP relevant any ocular maligancies	after BD113vVLP administration	12 months
Secondary	Changes in BCVA	at M3, M6 and M12 after BD113 vVLP administration from baseline, not applicable to group 1.	12 months
Secondary	Changes in visual fields	at M3, M6 and M12 after BD113 vVLP administration from baseline, not applicable to group 1.	12 months
Secondary	Changes in RNFL	at M3, M6 and M12 after BD113 vVLP administration from baseline, not applicable to group 1.	12 months
Secondary	p24 and Cas9 proteins concentration in aqueous humor	at 0h and M1 after BD113vVLP administration	12 months
Secondary	Blood concentration of p24 and Cas9 proteins	at 0h and D7 after BD113vVLP administration	1 month
Secondary	Blood antibodies of anti-p24 protein and anti-Cas9 protein	at 6 and 12 months after BD113vVLP administration	12 months