Gene Therapy for Blindness Caused by Choroideremia

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

- Primary objective: To assess the safety and tolerability of the AAV.REP1 vector, administered at two different doses to the retina in 12 patients with a diagnosis of choroideremia.

- Secondary Objective: To identify any therapeutic benefit as evidenced by a slowing down of the retinal degeneration assessed by functional and anatomical methods in the treated eye compared to the control eye 24 months after gene delivery.

Study Overview

• Status: Completed
• Conditions: Choroideremia
• Intervention / Treatment: Drug: rAAV2.REP1

Detailed Description

Detailed description may be found in the following scientific publication:

Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial, The Lancet, Volume 383, Issue 9923, Pages 1129 - 1137 (29 March 2014).

Links: www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62117-0/abstract ; http://dx.doi.org/doi:10.1016/S0140-6736(13)62117-0

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hospital NHS Foundation Trust
  • Manchester, United Kingdom, M13 9WL
    • St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • Oxford Radcliffe Hospitals NHS Trust
  • Southampton, United Kingdom, SO16 6YD
    • Eye Unit, Southampton University Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study,
• Male aged 18 years or above,
• Diagnosed with choroideraemia and in good health,
• Active disease with SLO changes visible within the macula region,
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study,
• Vision at least 6/60 or better in the study eye.

Exclusion Criteria:

• Female and child participants (under the age of 18),
• Men unwilling to use barrier contraception methods, if relevant,
• Previous history of retinal surgery or ocular inflammatory disease (uveitis),
• Grossly asymmetrical disease or other ocular morbidity which might confound use of the fellow eye as a long-term control,
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study,
• Participants who have participated in another research study involving an investigational product in the previous 12 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dose 1; Dose 1 = single subretinal injection of vector suspension containing approximately 10e10 rAAV2.REP1 genome particles. Six patients have now received Dose 1.	Drug: rAAV2.REP1; Single subretinal injection of rAAV2.REP1 vector suspension containing 10e12 genome particles per ml. Dose 1 = dose containing approximately 10e10 rAAV2.REP1 genome particles. Dose 2 = dose containing approximately 10e11 rAAV2.REP1 genome particles.; Other Names: Adeno-associated viral vector
EXPERIMENTAL: Dose 2; Dose 2 = single subretinal injection of vector suspension containing approximately 10e11 rAAV2.REP1 genome particles. Three patients thus far have received Dose 2.	Drug: rAAV2.REP1; Single subretinal injection of rAAV2.REP1 vector suspension containing 10e12 genome particles per ml. Dose 1 = dose containing approximately 10e10 rAAV2.REP1 genome particles. Dose 2 = dose containing approximately 10e11 rAAV2.REP1 genome particles.; Other Names: Adeno-associated viral vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual acuity	Best corrected visual acuity, following cataract surgery if indicated	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microperimetry, OCT and fundus autofluorescence	Structure function correlations at the margins of the retinal degeneration	24 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: University College, London; University of Southampton; Moorfields Eye Hospital NHS Foundation Trust; Manchester University NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; University of Manchester; Oxford University Hospitals NHS Trust
• Investigators: Study Chair: Robert E MacLaren, MB ChB DPhil, University of Oxford, Oxford Radcliffe Hospitals NHS Trust and Moorfields Eye Hospital; Principal Investigator: Miguel C Seabra, MD PhD, Imperial College London; Principal Investigator: Andrew R Webster, MD, UCL Institute of Ophthalmology and Moorfields Eye Hospital; Principal Investigator: Susan M Downes, MD, Oxford University Hospitals NHS Trust; Principal Investigator: Graeme C Black, MB BCh DPhil, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust; Principal Investigator: Andrew J Lotery, MD, University of Southampton and Southampton University Hospitals Trust; Principal Investigator: Len W Seymour, PhD, University of Oxford; Principal Investigator: Tanya Tolmachova, PhD, Imperial College London

Publications and helpful links

General Publications

• Simunovic MP, Jolly JK, Xue K, Edwards TL, Groppe M, Downes SM, MacLaren RE. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6033-6039. doi: 10.1167/iovs.16-20230.
• Xue K, Oldani M, Jolly JK, Edwards TL, Groppe M, Downes SM, MacLaren RE. Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia. Invest Ophthalmol Vis Sci. 2016 Jul 1;57(8):3674-84. doi: 10.1167/iovs.15-18364.
• Seitz IP, Zhour A, Kohl S, Llavona P, Peter T, Wilhelm B, Zrenner E, Ueffing M, Bartz-Schmidt KU, Fischer MD. Multimodal assessment of choroideremia patients defines pre-treatment characteristics. Graefes Arch Clin Exp Ophthalmol. 2015 Dec;253(12):2143-50. doi: 10.1007/s00417-015-2976-4. Epub 2015 Mar 7.
• MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Mar 29;383(9923):1129-37. doi: 10.1016/S0140-6736(13)62117-0. Epub 2014 Jan 16.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): October 1, 2017
• Study Completion (ACTUAL): October 1, 2017

Study Registration Dates

• First Submitted: October 21, 2011
• First Submitted That Met QC Criteria: October 27, 2011
• First Posted (ESTIMATE): October 28, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 17, 2017
• Last Update Submitted That Met QC Criteria: November 16, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: retinitis pigmentosa; Tapetoretinal degeneration, choroideraemia, X-linked
• Additional Relevant MeSH Terms: Eye Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Uveal Diseases; Eye Diseases, Hereditary; Choroid Diseases; Choroideremia
• Other Study ID Numbers: CHM09/01; 2009-014617-27 (EUDRACT_NUMBER)