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Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations

Primary Purpose

Leber Congenital Amaurosis

Status
Completed
Phase
Phase 1
Locations
Israel
Study Type
Interventional
Intervention
rAAV2-hRPE65
Sponsored by
Hadassah Medical Organization
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leber Congenital Amaurosis focused on measuring Leber congenital amaurosis, LCA, RPE65, RPE65-associated Leber congenital amaurosis, Retinal disease due to RPE65 mutations

Eligibility Criteria

8 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Retinal disease caused by homozygous or compound heterozygote RPE65 mutations;
  • Clinical diagnosis of Leber congenital amaurosis (LCA) with severely impaired visual and retinal function, and best corrected visual acuity of 20/50 or worse in the study eye;
  • Ability to perform tests of visual and retinal function;
  • Good general health;
  • Ability to comply with research procedures;
  • Specific for Cohort 1 and 2: 18 years of age and older;
  • Specific for Cohort 3: Over 8 years of age;

Exclusion Criteria:

  • Immune deficiency or use of immunosuppressive medications;
  • Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints (for example, glaucoma or ocular media opacities);
  • Complicating systemic diseases;
  • Impaired coagulation or use of anti-platelet agents within 7 days prior to study agent administration;
  • Pregnancy or breastfeeding;
  • Individuals (males and females) of childbearing potential who are unwilling to use effective contraception for 1 year following agent administration and barrier contraception for 3 months following agent administration;
  • Any other condition that would prevent a subject from completing follow-up examinations during the course of the study;
  • Any other condition that, in the opinion of the investigator, makes the subject unsuitable for the study;
  • Current or recent participation in any other research protocol involving investigational agents or therapies, including recent (within past 6 months) receipt of an investigational biologic therapeutic agent.

Subjects will not be excluded based on their gender, race or ethnicity.

Sites / Locations

  • Hadassah Medical Organization

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

rAAV2-hRPE65

Arm Description

Outcomes

Primary Outcome Measures

The primary outcome measure is ocular and systemic safety of the treatment.

Secondary Outcome Measures

Visual function, as quantified before and after vector administration.

Full Information

First Posted
January 12, 2009
Last Updated
April 8, 2018
Sponsor
Hadassah Medical Organization
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1. Study Identification

Unique Protocol Identification Number
NCT00821340
Brief Title
Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
Official Title
Phase I Trial of Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus (rAAV2-hRPE65) Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations
Study Type
Interventional

2. Study Status

Record Verification Date
February 2010
Overall Recruitment Status
Completed
Study Start Date
February 1, 2009 (Actual)
Primary Completion Date
June 29, 2016 (Actual)
Study Completion Date
January 1, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hadassah Medical Organization

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this clinical trial is to examine the safety of gene therapy for Lebers Congenital Amaurosis (LCA) caused by RPE65 mutations using a recombinant adeno-associated virus serotype 2 (rAAV2) vector carrying the human RPE65 (hRPE65) gene. Recently, three independent short-term gene therapy studies in humans with LCA due to RPE65 mutations were published, suggesting that subretinal delivery of rAAV virus carrying the RPE65 gene is safe. As a secondary outcome, improvement in visual function was observed in seven of the first nine treated patients. The proposed study is a similar open label, Phase I clinical trial of uniocular subretinal rAAV2-hRPE65 administration to individuals with RPE65-associated retinal disease. Two cohorts of three subjects each and one cohort of four subjects will be included in this trial. Cohort 1 and 2 will consist of individuals 18 years of age and older and Cohorts 3 will consist of individuals 8 years of age and older. In cohort 2, a larger volume of vector will be administered. Enrollment in Cohort 3 will begin only after confirming the safety of rAAV2-hRPE65 administration in the older group of participants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leber Congenital Amaurosis
Keywords
Leber congenital amaurosis, LCA, RPE65, RPE65-associated Leber congenital amaurosis, Retinal disease due to RPE65 mutations

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
rAAV2-hRPE65
Arm Type
Experimental
Intervention Type
Genetic
Intervention Name(s)
rAAV2-hRPE65
Intervention Description
Uniocular subretinal injections; relative doses: Cohort 1 - basic (lowest) viral dose; Cohort 2 - higher (1.5 times basic) viral dose; Cohort 3 - patients 8-17 years of age will receive basic viral dose; patients 18 years of age and over will receive higher dose;
Primary Outcome Measure Information:
Title
The primary outcome measure is ocular and systemic safety of the treatment.
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Visual function, as quantified before and after vector administration.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Retinal disease caused by homozygous or compound heterozygote RPE65 mutations; Clinical diagnosis of Leber congenital amaurosis (LCA) with severely impaired visual and retinal function, and best corrected visual acuity of 20/50 or worse in the study eye; Ability to perform tests of visual and retinal function; Good general health; Ability to comply with research procedures; Specific for Cohort 1 and 2: 18 years of age and older; Specific for Cohort 3: Over 8 years of age; Exclusion Criteria: Immune deficiency or use of immunosuppressive medications; Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints (for example, glaucoma or ocular media opacities); Complicating systemic diseases; Impaired coagulation or use of anti-platelet agents within 7 days prior to study agent administration; Pregnancy or breastfeeding; Individuals (males and females) of childbearing potential who are unwilling to use effective contraception for 1 year following agent administration and barrier contraception for 3 months following agent administration; Any other condition that would prevent a subject from completing follow-up examinations during the course of the study; Any other condition that, in the opinion of the investigator, makes the subject unsuitable for the study; Current or recent participation in any other research protocol involving investigational agents or therapies, including recent (within past 6 months) receipt of an investigational biologic therapeutic agent. Subjects will not be excluded based on their gender, race or ethnicity.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eyal Banin, MD, PhD
Organizational Affiliation
Hadassah Medical Organization
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hadassah Medical Organization
City
Jerusalem
ZIP/Postal Code
91120
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
16226919
Citation
Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005 Dec;12(6):1072-82. doi: 10.1016/j.ymthe.2005.08.008. Epub 2005 Oct 14.
Results Reference
background
PubMed Identifier
18441371
Citation
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9. doi: 10.1056/NEJMoa0802268. Epub 2008 Apr 27.
Results Reference
background
PubMed Identifier
18441370
Citation
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27.
Results Reference
background
PubMed Identifier
18441372
Citation
Miller JW. Preliminary results of gene therapy for retinal degeneration. N Engl J Med. 2008 May 22;358(21):2282-4. doi: 10.1056/NEJMe0803081. Epub 2008 Apr 27. No abstract available.
Results Reference
background
PubMed Identifier
18774912
Citation
Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90. doi: 10.1089/hum.2008.107.
Results Reference
background
PubMed Identifier
18809924
Citation
Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang JJ, Sumaroka A, Windsor EA, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15112-7. doi: 10.1073/pnas.0807027105. Epub 2008 Sep 22.
Results Reference
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Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations

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