Clinical trial NCT03872479: Single Ascending Dose Study in Participants With LCA10
Official title: 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")
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Leber Congenital Amaurosis 10
Inherited Retinal Dystrophies
Eye Diseases, Hereditary
Retinal Disease
Retinal Degeneration
Vision Disorders
Eye Disorders Congenital
Keywords: 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
Lead sponsor: Editas Medicine, Inc.
Sponsor class: INDUSTRY
First posted: 2019-03-13
Enrollment: 34
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Frequency of Adverse Events related to EDIT-101
timeFrame: 1 year
measure: Number of participants experiencing procedural related adverse events
timeFrame: 1 year
measure: Incidence of dose limiting toxicities
timeFrame: 1 year
Secondary outcomes:
measure: Maximum tolerated dose as determined by occurrence of dose limiting toxicities
timeFrame: 1 year
measure: Change from baseline in Mobility course score
timeFrame: 1 year
measure: Change from baseline in LogMAR measurement of BCVA
timeFrame: 1 year
measure: Change from baseline in pupillary response
timeFrame: 1 year
measure: Change from baseline in dark adapted visual sensitivity using Full field light sensitivity threshold (FST)
timeFrame: 1 year
measure: Change from baseline in macula thickness
timeFrame: 1 year
measure: Change from baseline in contrast sensitivity
timeFrame: 1 year
measure: Change from baseline in macular sensitivity as measured by microperimetry
timeFrame: 1 year
measure: Change from baseline in color vision score using the Farnsworth 15 score
timeFrame: 1 year
measure: Change from baseline in QOL score for Age <8 years using the Children's Visual Function Questionnaire
timeFrame: 1 year
measure: Change from baseline in QOL score for Age 8 to <18 years using the Impact of Vision Impairment for Children
timeFrame: 1 year
measure: 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
timeFrame: 1 year
measure: 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
timeFrame: 1 year
measure: Change from baseline in visual field using kinetic perimetry
timeFrame: 1 year
measure: Change from baseline in Patient Global Impressions of Change score
timeFrame: 1 year
measure: Change from baseline in gaze tracking
timeFrame: 1 year
Other outcomes:
Locations:
city: Miami
country: United States
facility: Bascom Palmer Eye Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary
state: Massachusetts
city: Ann Arbor
country: United States
facility: W.K. Kellogg Eye Center - University of Michigan
state: Michigan
city: Portland
country: United States
facility: Casey Eye Institute - OSHU
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
References:
citation: Harvey JP, Sladen PE, Yu-Wai-Man P, Cheetham ME. Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development. J Neuroophthalmol. 2022 Mar 1;42(1):35-44. doi: 10.1097/WNO.0000000000001375. Epub 2021 Sep 30.
citation: Zhang X, Zhang D, Thompson JA, Chen SC, Huang Z, Jennings L, McLaren TL, Lamey TM, De Roach JN, Chen FK, McLenachan S. Gene correction of the CLN3 c.175G>A variant in patient-derived induced pluripotent stem cells prevents pathological changes in retinal organoids. Mol Genet Genomic Med. 2021 Mar;9(3):e1601. doi: 10.1002/mgg3.1601. Epub 2021 Jan 26.