Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis
Primary Purpose
Viral Keratitis, Blindness Eye, Herpes Simplex Virus Infection
Status
Completed
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
BD111 Adult single group Dose
Sponsored by
About this trial
This is an interventional treatment trial for Viral Keratitis focused on measuring Herpes simplex virus type 1 (HSV-1), CRISPR/Cas9 mRNA, instantaneous gene editing
Eligibility Criteria
Inclusion Criteria:
Patients (replase) with refractory keratitis caused by herpes virus type I who has had at least one time failed corneal transplant.
- Age between 18 to 70 years.
- No systemic immune eye disease.
- Good eyelid structure and blink function.
- Exists the potential of visual recovery by evaluation of ocular structure and function.
- 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.
- Patients who are obviously suffering from relapse HSV infections with corneal perforation, requiring corneal transplantation;
- No history of corneal trauma.
- Subjects or their legal guardians voluntarily participate in this study, sign informed consent, good compliance and cooperation with follow-up visits.
Exclusion Criteria:
- Lacrimal coating and blink function loss.
- Schirmer's test result is less than 2mm for severe dry eye disease.
- Pregnant and lactating women (pregnancy defined in this study as positive urine pregnancy test).
- Currently is involved in clinical trials of other drugs or medical devices.
- 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.
- Ocular surface malignant tumor.
- 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.
- current in an infectious disease requiring oral, intramuscular or intravenous administration.
- Patients with systemic immune diseases.
- Any uncontrolled clinical problems (such as severe mental, neurological, cardiovascular, respiratory and other systemic diseases and malignant neoplasms).
- Not effective contraception.
- In uncontrolled hypertension, systolic is no less than 160 mmhg, diastolic is no less than 100 mmhg.
- In uncontrolled diabetes, fasting glucose is no less than 10.0umol/L.
- Renal insufficiency, serum creatinine is more than 133umol/L.
- Arrhythmia, myocardial ischemia, myocardial infarction (diagnosed by electrocardiogram).
- Liver dysfunction, al ANINE aminotransferase and aspartate aminotransferase levels are higher than 80 IU/L.
- Platelet level is below 100,000 /uL or above 450,000 /uL.
- Hemoglobin level is below 10.0g/dL (male) or 9.0g/dL (female).
- No anticoagulant was used, prothrombin time is higher than 16s, and thrombin time of activated part is higher than 50s.
- HIV infection (HIV-positive).
- Subjects lack compliance with the study or the ability to sign informed consent.
- 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).
- Administration of Glucocorticoids and other systemic immunosuppressive drugs.
- The investigator judges other conditions unsuitable for the trial
Sites / Locations
- Eye & Ent Hospital of Fudan University
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
BD111 Adults single group Dose
Arm Description
Administered by corneal injection surgery. Dosage form:injection solution. Dose:200uL. Frequency of administration: one time injection.
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
Corneal graft survival time
Observe the survival time of grafted cornea in participants, whether the grafted cornea is transparency or opacity.
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.
Concentration of dose limiting toxicities
Observe and record AE,SAE incidence of dose limiting toxicities related with BD111 administration.
Concentration of maximum tolerated dose
Observe and record AE,SAE at maximum tolerated dose when occurs dose limiting toxicities.
Full Information
NCT ID
NCT04560790
First Posted
September 17, 2020
Last Updated
August 20, 2022
Sponsor
Shanghai BDgene Co., Ltd.
Collaborators
Eye & ENT Hospital of Fudan University
1. Study Identification
Unique Protocol Identification Number
NCT04560790
Brief Title
Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis
Official Title
CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy Assisted Corneal Transplantation in the Treatment of Refractory Viral Keratitis
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
November 4, 2020 (Actual)
Primary Completion Date
July 5, 2022 (Actual)
Study Completion Date
July 5, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai BDgene Co., Ltd.
Collaborators
Eye & ENT Hospital of Fudan University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Viral Keratitis, Blindness Eye, Herpes Simplex Virus Infection, Cornea
Keywords
Herpes simplex virus type 1 (HSV-1), CRISPR/Cas9 mRNA, instantaneous gene editing
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Single group target value: Since there is no similar products approved on the market and there is no similar comparative treatment methods, the single group target value method is adopted
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BD111 Adults single group Dose
Arm Type
Experimental
Arm Description
Administered by corneal injection surgery. Dosage form:injection solution. Dose:200uL. Frequency of administration: one time injection.
Intervention Type
Drug
Intervention Name(s)
BD111 Adult single group Dose
Intervention Description
3-6 Participants will receive a single group dose administered via corneal injection in the study eye.
Primary Outcome Measure Information:
Title
Effective clearance of HSV-1 genome
Description
Judge HSV-1 genome clearance effective according to DNA sequencing results by methods of Plaque assay,Elisa,PCR etc.
Time Frame
12 months
Title
Rate of reblindness in 3 participants with Refractory HSV Keratitis
Description
180 days after corneal surgical, calculate rate of reblindness of treated eye in 3 participants.
Time Frame
12 months
Title
HSV-1 virus testing outcome of the intervention eye
Description
Herpes virus content before and after treatment were determinated by methods of plaque assay, ELISA, PCR etc. Compare the viral content changes with baseline.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Corneal graft survival time
Description
Observe the survival time of grafted cornea in participants, whether the grafted cornea is transparency or opacity.
Time Frame
12 months
Title
Visual improvement compared with baseline
Description
Judge the visual recovery progress according to visual examination results on day 3±1,7±2,30±7,90±14,180±21,360±31.
Time Frame
12 months
Title
Concentration of dose limiting toxicities
Description
Observe and record AE,SAE incidence of dose limiting toxicities related with BD111 administration.
Time Frame
12 months
Title
Concentration of maximum tolerated dose
Description
Observe and record AE,SAE at maximum tolerated dose when occurs dose limiting toxicities.
Time Frame
12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients (replase) with refractory keratitis caused by herpes virus type I who has had at least one time failed corneal transplant.
Age between 18 to 70 years.
No systemic immune eye disease.
Good eyelid structure and blink function.
Exists the potential of visual recovery by evaluation of ocular structure and function.
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.
Patients who are obviously suffering from relapse HSV infections with corneal perforation, requiring corneal transplantation;
No history of corneal trauma.
Subjects or their legal guardians voluntarily participate in this study, sign informed consent, good compliance and cooperation with follow-up visits.
Exclusion Criteria:
Lacrimal coating and blink function loss.
Schirmer's test result is less than 2mm for severe dry eye disease.
Pregnant and lactating women (pregnancy defined in this study as positive urine pregnancy test).
Currently is involved in clinical trials of other drugs or medical devices.
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.
Ocular surface malignant tumor.
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.
current in an infectious disease requiring oral, intramuscular or intravenous administration.
Patients with systemic immune diseases.
Any uncontrolled clinical problems (such as severe mental, neurological, cardiovascular, respiratory and other systemic diseases and malignant neoplasms).
Not effective contraception.
In uncontrolled hypertension, systolic is no less than 160 mmhg, diastolic is no less than 100 mmhg.
In uncontrolled diabetes, fasting glucose is no less than 10.0umol/L.
Renal insufficiency, serum creatinine is more than 133umol/L.
Arrhythmia, myocardial ischemia, myocardial infarction (diagnosed by electrocardiogram).
Liver dysfunction, al ANINE aminotransferase and aspartate aminotransferase levels are higher than 80 IU/L.
Platelet level is below 100,000 /uL or above 450,000 /uL.
Hemoglobin level is below 10.0g/dL (male) or 9.0g/dL (female).
No anticoagulant was used, prothrombin time is higher than 16s, and thrombin time of activated part is higher than 50s.
HIV infection (HIV-positive).
Subjects lack compliance with the study or the ability to sign informed consent.
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).
Administration of Glucocorticoids and other systemic immunosuppressive drugs.
The investigator judges other conditions unsuitable for the trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yujia Cai, PhD
Organizational Affiliation
Shanghai BDgene Co., Ltd.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Eye & Ent Hospital of Fudan University
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200000
Country
China
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis
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