CEP290-gene mutation and inherited retinal degeneration
Conditions
Interventions
Participants will receive a single study intervention treatment (EDIT-101
administered, following vitrectomy, via subretinal injection) in one eye (the
study eye). The study eye will be determined a
Sponsors
Editas Medicine, Inc.
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: -Adult participants enrolling in Cohorts 1, 2, or 3 must be at least 18 years of age at the time of informed consent. Pediatric participants enrolling in Cohorts 4 or 5 must be 3 to 17 years of age, inclusive, at the time of informed consent. -CEP290-related retinal degeneration caused by a homozygous or compound heterozygous mutation involving c.2991+1655A>G in IVS26 of the CEP290 gene confirmed by DNA sequencing (ie, 1 or 2 intron 26 c.2991+1655A>G mutations) and 100% match for both gRNA and PAM sequences. -Male or Female. -A sexually mature male participant must agree to use contraception as detailed in Section 10.7 of this protocol from the time of informed consent through at least 12 months after study intervention, and to refrain from donating sperm during this period. -A female participant is eligible to participate if she is not pregnant (has a negative urine pregnancy result prior to study intervention), not breastfeeding, and at least one of the following conditions applies: Not a WOCBP as defined in Protocol Section 10.7, OR A WOCBP, or who reaches childbearing potential during the study, who agrees to follow the contraceptive guidance in Protocol Section 10.7 from the time of informed consent through at least 12 months after study intervention. -The participant (or guardian, in the case of a minor) must provide written informed consent prior to any study related procedures. Minors must provide assent in accordance with country and local regulations, as applicable. -Both eyes must be at least LP. The study eye will be the worse seeing eye and must meet the following BCVA criteria: Cohort 1: BWD, WFP, or LP Cohorts 2 - 5: LP to 0.4 logMAR (20/50 Snellen equivalent). ). Note: The sentinel participant in each of these cohorts 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. Subsequent participants in each cohort will have LP to 0.4 logMAR (20/50 Snellen equivalent) best-corrected visual acuity in the study eye. If both eyes have the same BCVA but the worse seeing eye (as determined by the participant and the examiner) does not meet the above criteria, the better seeing eye may be designated as the study eye as long as the participant agrees and the better seeing eye meets all eligibility criteria. -Photoreceptor ONL identifiable in fovea by spectral domain OCT in the study eye. -Able, as assessed by the investigator, and willing to complete study assessments and follow study instructions for the duration of the study. -If currently enrolled in Study EDIT-NHS01 (the Natural History Study of CEP290-Related Retinal Degeneration), the participant must agree to complete the early termination visit for that study, and be withdrawn from that study, before enrolling in this study.
Exclusion criteria
Exclusion criteria: -Other known disease-causing mutations documented in the participant's medical history or identified through the retinal dystrophy gene panel evaluation performed at screening (including but not limited to bi-allelic mutations in other genes known to cause LCA) that, in the opinion of the investigator, would interfere with the potential therapeutic effect of the investigational product or the quality of the assessments. -Achieves a passing score for the Visual Function Navigation course at the maximum level of difficulty (ie, passes the most challenging Visual Function Navigation course under the dimmest lighting conditions) with either eye independently or both eyes together. -In either eye, cataract surgery in the last 3 months before the screening visit. -In either eye, any active ocular/intraocular infection or inflammation (such as blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, idiopathic or autoimmune-associated uveitis, or herpetic lesions), assessed at screening. -In either eye, history of steroid-responsive intraocular pressure increases such that the affected eye had a pressure > 25 mm Hg following corticosteroid exposure despite topical intraocular-pressure-lowering pharmacologic therapy. -In either eye, Argus retinal implant. -In the study eye, absence of clear ocular media and adequate pupil dilation, assessed at screening, to permit good quality OCT images. -In the study eye, presence of vitreous hemorrhage. -In the study eye, any history of rhegmatogenous retinal detachment. -In the study eye, spherical equivalent of the refractive error demonstrating more than -8 diopters of myopia and more than +6 diopters of hyperopia (prior to cataract or refractive surgery), assessed at screening. -Uncontrolled diabetes mellitus (hemoglobin A1c >=10%) in the last 3 months before the screening visit or at screening. -Active gastric ulcer at screening. -Use of systemic immunosuppressive medications for any chronic disease in the last 3 months before the screening visit, or during the screening period. -Any vaccination/immunization in the last 28 days before screening, or during the screening period. -An inability or unwillingness to take the course of oral prednisone that is required in this study. -Current enrollment in an investigational interventional drug or device study (ocular or non-ocular) or participation in such a study within 6 months before the screening visit. (This does not include observational studies. Prior or current participation in Study EDIT-NHS01 is not an exclusion.) -Received prior gene therapy or oligonucleotide treatment of any kind. -The participant has a condition or is in a situation which, in the investigator's or operating surgeon's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant's participation in the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| • Incidence of DLT, as detailed in Section 8.3.8.1 of the protocol • Frequency of AEs related to EDIT-101 • Number of procedural related AEs | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary -Maximum tolerated dose as determined by DLT -Change from baseline in the following parameters: * Visual Function Navigation course score of the study eye, contralateral eye, and both eyes together * logMAR measurement of BCVA * Pupil size in dark (maximum diameter), pupil size in light (minimum diameter), mean pupil constriction velocity, maximum pupil constriction velocity, amount of constriction after stimulus, percent of constriction after stimulus * Gaze tracking * Dark adapted visual sensitivity to white, red, and blue light * The thickness of the ONL and integrity of the ellipsoid zone * LogMAR measurement of contrast sensitivity. * Macular sensitivity * Visual field * Farnsworth 15 score * QoL questionnaires * Global Impressions of Change * Global Impressions of Severity Exploratory • Detection of anti-drug antibodies to AAV5 (BAB by ELISA and NAB using a cell-based assay) and Cas9 (BAB by ELISA) • Detection of T cell response to AAV5 and Cas9 by ELISPOT • Quantification of vector DNA in blood, nasal mucosa, semen, and tears • Changes in area of autofluorescence | — |
Countries
Netherlands
Outcome results
None listed