Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis

CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy Assisted Corneal Transplantation in the Treatment of Refractory Viral Keratitis

The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of BD111 CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy administered via corneal injection in participants with refractory herpetic viral keratitis.

Study Overview

• Status: Completed
• Conditions: Cornea; Herpes Simplex Virus Infection; Viral Keratitis; Blindness Eye
• Intervention / Treatment: Drug: BD111 Adult single group Dose

Detailed Description

This is an open-label, single ascending dose study of BD111 in adult (ages 18 to 70) participants with refractory herpetic viral keratitis. Approximately 6 participants will be enrolled.BD111 is a novel gene editing product designed to clear Herpes simplex virus type I (HSV-1) that results in herpetic stromal keratitis in both acute and recurrent infection models which is the leading factor for infectious blindness.

The follow-up period was 360 days, and the patients will be followed up 3±1 days, 7±2 days, 30±7 days, 90±14 days, 180±21 days, and 360+31 days after treatment.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200000
      • Eye & ENT Hospital of Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients (replase) with refractory keratitis caused by herpes virus type I who has had at least one time failed corneal transplant.

1. Age between 18 to 70 years.
2. No systemic immune eye disease.
3. Good eyelid structure and blink function.
4. Exists the potential of visual recovery by evaluation of ocular structure and function.
5. Patients with refractory keratitis who are repeatedly infected with HSV-1 virus (more than three times per year) and resistant to topical or systemic anti-viral agents, with no response to regular immunosuppressive agents.
6. Patients who are obviously suffering from relapse HSV infections with corneal perforation, requiring corneal transplantation;
7. No history of corneal trauma.
8. Subjects or their legal guardians voluntarily participate in this study, sign informed consent, good compliance and cooperation with follow-up visits.

Exclusion Criteria:

1. Lacrimal coating and blink function loss.
2. Schirmer's test result is less than 2mm for severe dry eye disease.
3. Pregnant and lactating women (pregnancy defined in this study as positive urine pregnancy test).
4. Currently is involved in clinical trials of other drugs or medical devices.
5. Active eye infection (including but not limited to: blepharitis, infectious conjunctivitis, keratitis, sclerotitis, endophthalmitis) in target eye or contralateral eye within 30 days prior to enrollment.
6. Ocular surface malignant tumor.
7. A history of allergic reaction or allergy to sodium luciferin, allergy to protein products used for treatment or diagnosis, allergy to ≥ 2 drugs or non-drug factors, or current allergic disease.
8. current in an infectious disease requiring oral, intramuscular or intravenous administration.
9. Patients with systemic immune diseases.
10. Any uncontrolled clinical problems (such as severe mental, neurological, cardiovascular, respiratory and other systemic diseases and malignant neoplasms).
11. Not effective contraception.
12. In uncontrolled hypertension, systolic is no less than 160 mmhg, diastolic is no less than 100 mmhg.
13. In uncontrolled diabetes, fasting glucose is no less than 10.0umol/L.
14. Renal insufficiency, serum creatinine is more than 133umol/L.
15. Arrhythmia, myocardial ischemia, myocardial infarction (diagnosed by electrocardiogram).
16. Liver dysfunction, al ANINE aminotransferase and aspartate aminotransferase levels are higher than 80 IU/L.
17. Platelet level is below 100,000 /uL or above 450,000 /uL.
18. Hemoglobin level is below 10.0g/dL (male) or 9.0g/dL (female).
19. No anticoagulant was used, prothrombin time is higher than 16s, and thrombin time of activated part is higher than 50s.
20. HIV infection (HIV-positive).
21. Subjects lack compliance with the study or the ability to sign informed consent.
22. There are currently signs of systemic infection, including fever and ongoing antibiotic treatment (in this study, systemic infection was defined as deviation from normal values of white blood cells, lymphocytes, and neutrophils on routine blood tests).
23. Administration of Glucocorticoids and other systemic immunosuppressive drugs.
24. The investigator judges other conditions unsuitable for the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BD111 Adults single group Dose; Administered by corneal injection surgery. Dosage form:injection solution. Dose:200uL. Frequency of administration: one time injection.	Drug: BD111 Adult single group Dose; 3-6 Participants will receive a single group dose administered via corneal injection in the study eye.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effective clearance of HSV-1 genome	Judge HSV-1 genome clearance effective according to DNA sequencing results by methods of Plaque assay,Elisa,PCR etc.	12 months
Rate of reblindness in 3 participants with Refractory HSV Keratitis	180 days after corneal surgical, calculate rate of reblindness of treated eye in 3 participants.	12 months
HSV-1 virus testing outcome of the intervention eye	Herpes virus content before and after treatment were determinated by methods of plaque assay, ELISA, PCR etc. Compare the viral content changes with baseline.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corneal graft survival time	Observe the survival time of grafted cornea in participants, whether the grafted cornea is transparency or opacity.	12 months
Visual improvement compared with baseline	Judge the visual recovery progress according to visual examination results on day 3±1，7±2，30±7，90±14，180±21，360±31.	12 months
Concentration of dose limiting toxicities	Observe and record AE,SAE incidence of dose limiting toxicities related with BD111 administration.	12 months
Concentration of maximum tolerated dose	Observe and record AE,SAE at maximum tolerated dose when occurs dose limiting toxicities.	12 months

Collaborators and Investigators

• Sponsor: Shanghai BDgene Co., Ltd.
• Collaborators: Eye & ENT Hospital of Fudan University
• Investigators: Principal Investigator: Yujia Cai, PhD, Shanghai BDgene Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2020
• Primary Completion (Actual): July 5, 2022
• Study Completion (Actual): July 5, 2022

Study Registration Dates

• First Submitted: September 17, 2020
• First Submitted That Met QC Criteria: September 17, 2020
• First Posted (Actual): September 23, 2020

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 20, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Herpes simplex virus type 1 (HSV-1); CRISPR/Cas9 mRNA; instantaneous gene editing
• Additional Relevant MeSH Terms: Nervous System Diseases; Skin Diseases; Virus Diseases; Infections; Eye Diseases; Neurologic Manifestations; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Corneal Diseases; Sensation Disorders; Herpesviridae Infections; Vision Disorders; Keratitis; Herpes Simplex; Blindness
• Other Study ID Numbers: JYMS-CXL#02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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