Single Ascending Dose Study in Participants With LCA10

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of EDIT-101 administered via subretinal injection in participants with LCA10 caused by a homozygous or compound heterozygous mutation involving c.2991+1655A>G in intron 26 of the CEP290 gene (LCA10-IVS26).

Detailed Description
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This is an open-label, single ascending dose study of EDIT-101 in adult and pediatric (ie, ages 3 to 17) participants with LCA10-IVS26. Up to 34 participants will be enrolled in up to 5 cohorts to evaluate up to 3 dose levels of EDIT-101 in this study. EDIT-101 is a novel gene editing product designed to eliminate the mutation on the CEP290 gene that results in the retinal degeneration that defines LCA10-IVS26.

Official Title
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Open-Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Efficacy of EDIT-101 in Adult and Pediatric Participants With Leber Congenital Amaurosis Type 10 (LCA10), With Centrosomal Protein 290 (CEP290)-Related Retinal Degeneration Caused by a Compound Heterozygous or Homozygous Mutation Involving c.2991+1655A>G in Intron 26 (IVS26) of the CEP290 Gene (LCA10-IVS26)

Conditions
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Leber Congenital Amaurosis 10, Inherited Retinal Dystrophies, Eye Diseases, Hereditary, Retinal Disease, Retinal Degeneration, Vision Disorders, Eye Disorders Congenital

Intervention / Treatment
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* Drug: EDIT-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female At least 3 years of age at screening with CEP290-related retinal degeneration caused by a homozygous or compound heterozygous mutation involving c.2991+1655A>G in IVS26 of the CEP290 gene. Visual Acuity: Sentinel participant will have severe vision loss with a logMAR BCVA of ≥1.6 to 3.9 (20/800 or worse to LP) in the study eye Non-sentinel participants must have BCVA between 1.0 - 3.0 logMAR in the study eye Exclusion Criteria: Other known disease-causing mutations Achieves a passing score for the mobility course at the most difficult level In either eye, active systemic or ocular/intraocular infection or inflammation In either eye, history of steroid-responsive intraocular pressure with increases > 25 mm Hg following corticosteroid exposure Any vaccination/immunization in the last 28 days before screening Inability or unwillingness to take oral prednisone Prior gene therapy or oligonucleotide treatment

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adults Low Dose<br>Single dose of EDIT-101 administered by subretinal injection surgery | Drug: EDIT-101<br>* Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.<br>|
| Experimental: Adults Middle Dose<br>Single dose of EDIT-101 administered by subretinal injection surgery | Drug: EDIT-101<br>* Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.<br>|
| Experimental: Adults High Dose<br>Single dose of EDIT-101 administered by subretinal injection surgery | Drug: EDIT-101<br>* Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.<br>|
| Experimental: Pediatric Middle Dose<br>Single dose of EDIT-101 administered by subretinal injection surgery | Drug: EDIT-101<br>* Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.<br>|
| Experimental: Pediatric High Dose<br>Single dose of EDIT-101 administered by subretinal injection surgery | Drug: EDIT-101<br>* Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events related to EDIT-101 |  | 1 year | 
| Number of participants experiencing procedural related adverse events |  | 1 year | 
| Incidence of dose limiting toxicities |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose as determined by occurrence of dose limiting toxicities |  | 1 year | 
| Change from baseline in Mobility course score | Testing the subjects visual function by having the subject walk through obstacle courses. Courses will have different levels of difficulty depending on the light levels of the room and the contrast of the objects in the room. | 1 year | 
| Change from baseline in LogMAR measurement of BCVA | The test will evaluate visual acuity in ranges from light perception to normal vision. | 1 year | 
| Change from baseline in pupillary response | Measuring the change in pupil diameter in response to a light stimulus. | 1 year | 
| Change from baseline in dark adapted visual sensitivity using Full field light sensitivity threshold (FST) | Flashes of light of varying luminance are presented to the eye and the subject reports is the flash was seen. | 1 year | 
| Change from baseline in macula thickness |  | 1 year | 
| Change from baseline in contrast sensitivity | The Lea symbols chart will be used for subjects under age 6 and the Pelli-Robson chart for all other subjects. The images or letters on the charts are in decreasing contrast. | 1 year | 
| Change from baseline in macular sensitivity as measured by microperimetry | Visual field test measuring the amount of light perceived in specific parts of the macula. | 1 year | 
| Change from baseline in color vision score using the Farnsworth 15 score | The Farnsworth D15 tests for congenital and acquired color vision defects. Fifteen color discs will be arranged by the subject. Scoring is accomplished by recording the sequence selected by the patient on a copy of the score sheet. A patient with a color vision deficiency will arrange the color discs in a different order than a person with normal color vision. | 1 year | 
| Change from baseline in QOL score for Age <8 years using the Children's Visual Function Questionnaire |  | 1 year | 
| Change from baseline in QOL score for Age 8 to <18 years using the Impact of Vision Impairment for Children |  | 1 year | 
| Change from baseline in QOL score for Age >18 years if BCVA is worse than 1.0 logMAR in both eyes using the Impact of Vision Impairment for Very Low Vision |  | 1 year | 
| Change from baseline in QOL score for Age >18 years if BCVA is 1.0 logMAR or better in both eyes using the Impact of Vision Impairment |  | 1 year | 
| Change from baseline in visual field using kinetic perimetry | Kinetic perimetry looks as the visual field to identify regions of normal and abnormal sensitivity to light | 1 year | 
| Change from baseline in Patient Global Impressions of Change score | This QOL has 5 non-numeric choices for the subject to select how they believe their condition has changed. | 1 year | 
| Change from baseline in gaze tracking | Video clips of the eyes are used to measure eye position and stability over time. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CEP290, LCA10, Retinal degenerative diseases (RDD), Leber congenital amaurosis (LCA), Congenital Retinal Blindness, p.Cys998X, c.2991+1655A>G, CRISPR Treatment, Cas9 Protein, Eye Diseases Signs and Symptoms, Genetic Diseases, Inborn, Congenital Abnormalities, Eye Abnormalities, CRISPR-Cas9, CRISPR Associated Protein 9, Cas9 Enzyme