Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis

• Additional visual/retinal function tests [ Time Frame: One year ] [ Designated as safety issue: No ]
• Ophthalmic exams, physical exams, immunology studies, clinical labs, & adverse event recording [ Time Frame: Two years ] [ Designated as safety issue: Yes ]

• Additional visual/retinal function tests and ocular motility measurements [ Time Frame: Six months ] [ Designated as safety issue: No ]
• Ophthalmic exams, physical exams, immunology studies, clinical labs, & adverse event recording [ Time Frame: Six months ] [ Designated as safety issue: Yes ]

The study is a Phase 3, open-label, randomized controlled trial of gene therapy intervention by subretinal administration of AAV2-hRPE65v2. At least twenty-four subjects, three years of age or older, will be recruited. The intervention group will receive AAV2-hRPE65v2 vector at either The Children's Hospital of Philadelphia or University of Iowa to determine if it improves visual and retinal function in individuals with LCA2.

Leber congenital amaurosis (LCA) is a disease where part of the eye (the retina) is severely diseased. Usually it is detected in affected people within the first few months of life. LCA is incurable and untreatable and there is significantly poor vision at birth. Cells in the retina are lost over time in people with LCA which leads to total blindness. This study will focus on the form of LCA caused by changes (mutations) in DNA that makes a certain protein (called the 65 kDa retinal pigment epithelium (RPE)-specific protein, or RPE65). Clinical diagnosis is made by function tests of the eye. This can be confirmed by a special method of testing (molecular testing) to verify that the RPE65 is not correct.

This study uses a gene therapy vector made from an adeno-associated virus (AAV) called AAV2-hRPE65v2. Gene therapy refers to the incorporation of new DNA into cells with the goal of supplying a therapeutic gene or a gene that is missing or not functioning in the cell. The AAV parts of the gene therapy vector work as a delivery vehicle for getting the normal human RPE65 gene into the cells of the retina. An earlier clinical study of AAV2-hRPE65v2 was conducted based on the demonstration of safety and effectiveness of the vector in animals with a similar eye disease. The earlier clinical study tested three doses of the vector in twelve children and adults. The three doses were safe for the eye and the rest of the body in individuals as young as eight years old. AAV2-hRPE65v2 administration also led to increased vision in the subjects, with the youngest subjects showing the most improvement.

This study will deliver AAV2-hRPE65v2 vector to at least sixteen intervention group subjects, age three or older; subjects will receive the vector in both eyes via subretinal injections during surgeries (on separate days). The purpose of this research study is to assess the effectiveness and safety of the AAV2-hRPE65v2 gene therapy vector as a possible treatment for LCA2. The control group of at least eight subjects will be able to cross-over to the intervention group after one year, provided they still meet all eligibility criteria.

• Experimental: AAV2-hRPE65v2
  Intervention: Biological: AAV2-hRPE65v2
• No Intervention: Control

• Ashtari M, Cyckowski LL, Monroe JF, Marshall KA, Chung DC, Auricchio A, Simonelli F, Leroy BP, Maguire AM, Shindler KS, Bennett J. The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest. 2011 Jun 1;121(6):2160-8. Epub 2011 May 23. Erratum in: J Clin Invest. 2011 Jul 1;121(7):2945.
• Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010 Mar;18(3):643-50. Epub 2009 Dec 1.
• Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying GS, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA, Maguire AM. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012 Feb 8;4(120):120ra15.
• 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. Epub 2008 Apr 27.
• Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JI, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, McDonnell JW, Leroy BP, Simonelli F, Bennett J. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009 Nov 7;374(9701):1597-605. Epub 2009 Oct 23.

Inclusion Criteria:

• Willingness to adhere to protocol and long-term follow-up as evidenced by written informed consent or parental permission and subject assent (where applicable).
• Diagnosis of LCA due to RPE65 mutations; molecular diagnosis is to be performed, or confirmed, by a CLIA-approved laboratory.
• Age three years old or older.
• Visual acuity worse than 20/60 and/or visual field less than 20o in any meridian as measured by a III4e isopter or equivalent.
• Sufficient viable retinal cells as determined by non-invasive means, such as optical coherence tomography (OCT) and/or ophthalmoscopy. Must have either: 1) an area of retina within the posterior pole of >100 µm thickness shown on OCT; 2) ≥ 3 disc areas of retina without atrophy or pigmentary degeneration within the posterior pole; or 3) remaining visual field within 30 degrees of fixation as measured by a III4e isopter or equivalent.
• Subjects must be evaluable on mobility testing (the primary efficacy endpoint) to be eligible for the study. Evaluable is defined as: 1) The ability to perform mobility testing within the luminance range evaluated in the study. Individuals must receive an accuracy score of ≤ 1 during screening mobility testing at 400 lux or less to be eligible; individuals with an accuracy score of > 1 on all screening mobility test runs at 400 lux, or those who refuse to perform mobility testing at screening, will be excluded. (See Appendix 3 for a description of accuracy score.); 2) The inability to pass mobility testing at 1 lux. Individuals must fail screening mobility testing at 1 lux to be eligible; individuals that pass one or more screening mobility test runs at 1 lux will be excluded.

Exclusion Criteria:

• Unable or unwilling to meet requirements of the study, including receiving bilateral subretinal vector administrations.
• Any prior participation in a study in which a gene therapy vector was administered.
• Participation in a clinical study with an investigational drug in the past six months.
• Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme; individuals who discontinue use of these compounds for 18 months may become eligible.
• Prior intraocular surgery within six months.
• Known sensitivity to medications planned for use in the peri-operative period.
• Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (for example: radiation treatment of the orbit; leukemia with CNS/optic nerve involvement). Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (e.g., macular edema or proliferative changes). Also excluded would be subjects with immunodeficiency (acquired or congenital) as there could be susceptibility to opportunistic infection (such as CMV retinitis).
• Individuals of childbearing potential who are pregnant or unwilling to use effective contraception for four months following vector administration.
• Individuals incapable of performing mobility testing (the primary efficacy endpoint) for reason other than poor vision, including physical or attentional limitations.
• Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study or, in the opinion of the investigator, makes the potential subject unsuitable for the study.
• Subjects will not be excluded based on their gender, race, or ethnicity.