We propose a set of coordinated activities aimed at enabling the translation of a successful preclinical gene therapy for the CNGB3 form of achromatopsia into a clinical trial. This novel recombinant adeno-associated virus (rAAV) gene delivery reagent is a """"""""first in class"""""""" therapeutic agent to address the unmet vision needs of patients with CNGB3 related achromatopsia. To achieve this goal we propose six Specific Aims.
Aim 1 will optimize the rAAV-CNGB3 vector by systematically modifying each of the components (promoter, intron, cDNA and polyA) so that the vector does not exceed its optimal packaging capacity, is able to target all three cone subclasses, and has optimized codons that enable maximal efficacy at a minimum dose.
Aim 2 will produce rAAV-human CNGB3 vectors for use in animal studies in order to identify an optimal vector construct, which will then be produced for use in GLP safety studies and in clinical trials using a scalable, recombinant herpes simplex virus-based production method we developed that meets GMP standards and FDA requirements.
Aim 3 will evaluate an alternative serotype capsids and cone promoters for efficacy in a CNGB3-/- mouse model of achromatopsia. This will refine preliminary results suggesting that intravitreal administration of vector may lead to relevant transduction of cone photoreceptors. The optimal vector construct expressing human CNGB3 and ocular site of delivery will then be used to perform preliminary safety studies in nonhuman primates.
Aim 4 will evaluate CNGB3 achromatopsia patients using a battery of state-of-the-art methods to establish natural history, appropriate inclusion/exclusion criteria and endpoints appropriate for the clinica trial.
Aim 5 will the use the optimal vector from Aim 2 to perform GLP-compliant toxicology and biodistribution studies in rats and nonhuman primates. Prior to initiating these studies, we will conduct a pre-IND meeting with the FDA to review the proposed study design and manufacturing/release testing methods, to reach agreement on the studies that will satisfy IND requirements. Based on these data, in Aim 6 we will prepare and submit an IND to the FDA. The IND will include a protocol for a Phase 1/2 clinical trial whose design will be guided by results from the previous five Specific Aims.
The proposed study is designed to develop a safe and optimally effective AAV vector for delivering a normal copy of the human CNGB3 cDNA to the foveal cones of a cohort of pre-screened CNGB3 achromatopsia patients to restore their very poor visual acuity and debilitating light sensitivity that is presently untreatable.
|Gootwine, Elisha; Abu-Siam, Mazen; Obolensky, Alexey et al. (2017) Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep. Invest Ophthalmol Vis Sci 58:1577-1584|
|Langlo, Christopher S; Erker, Laura R; Parker, Maria et al. (2017) REPEATABILITY AND LONGITUDINAL ASSESSMENT OF FOVEAL CONE STRUCTURE IN CNGB3-ASSOCIATED ACHROMATOPSIA. Retina 37:1956-1966|
|Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter et al. (2016) Safety and Biodistribution Evaluation in CNGB3-Deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. Hum Gene Ther Clin Dev 27:27-36|
|Abozaid, Mortada A; Langlo, Christopher S; Dubis, Adam M et al. (2016) Reliability and Repeatability of Cone Density Measurements in Patients with Congenital Achromatopsia. Adv Exp Med Biol 854:277-83|
|Ye, Guo-Jie; Budzynski, Ewa; Sonnentag, Peter et al. (2016) Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. Hum Gene Ther Clin Dev :|
|Ye, Guo-Jie; Budzynski, Ewa; Sonnentag, Peter et al. (2016) Cone-Specific Promoters for Gene Therapy of Achromatopsia and Other Retinal Diseases. Hum Gene Ther 27:72-82|
|Langlo, Christopher S; Patterson, Emily J; Higgins, Brian P et al. (2016) Residual Foveal Cone Structure in CNGB3-Associated Achromatopsia. Invest Ophthalmol Vis Sci 57:3984-95|
|Ye, Guo-jie; Budzynski, Ewa; Sonnentag, Peter et al. (2016) Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. Hum Gene Ther Clin Dev 27:37-48|
|Ye, Guo-Jie; Budzynski, Ewa; Sonnentag, Peter et al. (2016) Safety and Biodistribution Evaluation in CNGB3-deficient Mice of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. Hum Gene Ther Clin Dev :|
|Boyd, R F; Boye, S L; Conlon, T J et al. (2016) Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs. Gene Ther 23:548-56|
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