Choroideremia Gene Therapy Clinical Trial

An Open Label Phase 2 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-associated Viral Vector (AAV2) Encoding Rab-escort Protein 1 (REP1)

Phase II gene therapy study, involving a total of 6 male patients with choroideremia. The study will be conducted at the Bascom Palmer Eye Institute, University of Miami. Patients will be required to attend a total of 11 study visits over a 24 month period with an additional 3 year follow-up.

This is a Phase II, open label study involving patients with a clinical phenotype of choroideremia and a confirmed CHM genotype. Following consent, patients will be required to attend an initial screening visit (Visit 1). Within 2 weeks of the screening visit patients will undergo a surgical procedure (Visit 2) under general anesthesia which will include a standard vitrectomy, retinal detachment and administration of a subretinal injection of AAV2-REP1 (1x1011 genome particles). Patients will be required to attend a further 9 study visits (Visits 3-11) over a 24 month period for functional, and anatomical assessments as well as monitoring of adverse events. The primary endpoint is the change from baseline in visual acuity in the study eye, compared to control eye. Secondary study endpoints are, change from baseline in autofluorescence evaluation, microperimetry readings and other anatomic and functional outcomes (all in the study eye compared to control eye). Secondary endpoints also include safety assessments to be conducted throughout the study. The fellow eyes of these patients will be utilized as controls in this study and will receive no study treatment.

Patients will have an assessment of visual acuity using the Early Treatment of Diabetic Retinopathy Study (ETDRS) vision charts in both eyes. Low Luminance BCVA was measured by placing a 2.0 log unit neutral density filter over the best correction for that eye and having the participant read the normally illuminated ETDRS chart and was reported as the number of letters read correctly (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). The study eye was defined as the eye that met inclusion/exclusion criteria with the worst standard BCVA. If the BCVA in both eyes was similar the Patient determines the worse eye be selected as the study eye. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening.

Measured in mm^2 by Fundus Autofluorescence and shows changes in the integrity and metabolism of retinal cells. A negative change from baseline indicates a decrease in size of the retained retina (worsening; disease progression).

Inclusion Criteria: 18 Years and older Male Able to give informed consent Genetically confirmed diagnosis of choroideremia Active disease visible clinically within the macula region Best-corrected visual acuity equal to or worse than 20/32 but better than or equal to 20/200 in the study eye. Exclusion Criteria: Female Under the age of 18 History of amblyopia in the study eye Men unwilling to use barrier contraception methods Relevant grossly asymmetrical disease or other ocular morbidity which might confound use of the fellow eye as a long-term control Any other significant ocular and non-ocular disease/disorder or retinal surgery Contraindication to use of medications or contrast agents Participated in research study involving an investigational product in the past 12 weeks Having had gene or cellular therapy at any time prior to this study.

Davis JL. The Blunt End: Surgical Challenges of Gene Therapy for Inherited Retinal Diseases. Am J Ophthalmol. 2018 Dec;196:xxv-xxix. doi: 10.1016/j.ajo.2018.08.038. Epub 2018 Sep 5.