Achromatopsia is a monogenic congenital retinal dystrophy that causes reduced visual acuity, extremely limited color vision discrimination, nystagmus and photophobia. It is inherited as an autosomal recessive trait. Four genes currently are known to cause the condition; CNGA3 and CNGB3 encoding the alpha- and beta-subunits, respectively, of the cyclic nucleotide gated channel type 3 (CNG3) on cone photoreceptors are responsible for the vast majority of the achromatopsia cases. Mutations in the CNGB3 genes alone account for more than 50% of individuals with achromatopsia, a retinal disorder that affects approximately 1 in every 33,000 individuals. The CNGA3 and CNGB3 proteins cooperate to form the heteromeric CNG3 conductance channel on the cone outer segment membrane. CNG3 channels are essential for converting light stimulation to activation of the cone photoreceptors and ultimately to daylight vision. In the absence of cone function, human vision is limited to rod function which is achromatic, resulting in poor acuity and saturation in bright illumination. Although achromatopsia historically was thought to be a condition in which cones were lacking or present in extremely reduced numbers, recent human studies show that a number of cones are still present even in older subjects with achromatopsia. Studies of CNGB3 and CNGA3 animal models also show that cones are present but have significant morphologic changes and progressive functional reduction with age. If cone function could be improved or restored in these subjects, they might recover augmented visual function. Gene therapy experiments have successfully treated achromat animal models, including both the naturally occurring CNGB3 mutation canine model and the CNGB3 knockout mouse model. A surprising observation was made during the gene therapy study of the CNGB3 dog achromat model: gene therapy could partially restore cone function on ERG testing in adult dogs, but only if animals were pretreated with ciliary neurotrophic factor (CNTF). Without prior treatment with CNTF, gene therapy was successful only for quite young dogs. This indicated that CNTF facilitated inducing a biological state in the adult cones in which they were receptive to gene rescue. More surprising was the finding that a bolus intravitreal injection of CNTF protein, without the CNGB3 gene vector, gave functional rescue of cones, and rescue persisted for several weeks until the CNTF from the bolus injection cleared. So, administration of CNTF protein alone, and without prior or subsequent gene vector delivery, supported recovery of light-stimulated activity of the cone photoreceptors in the CNGB3 achromat dog. CNTF is among the class of macro-biomolecules called neurotrophic factors which have been demonstrated to retard loss of photoreceptor cells during retinal degeneration. CNTF is effective in retarding vision loss from photoreceptor cell death in 13 animal models. A Phase 1 safety study in 2003-2006 was conducted at the NEI to investigate ocular delivery of CNTF in 10 subjects with end-stage retinitis pigmentosa. It passed appropriate safety milestones to mount Phase 2 studies, and the study indicated that CNTF possibly improved acuity performance in some subjects. The Phase 1 clinical trial observations and the animal studies provided the impetus for mounting a Phase 2 efficacy study for subjects with retinitis pigmentosa and dry AMD. The study design and outcome measures were based on the premise that CNTF could possibly improve visual function of cone photoreceptor cells. One major challenge is the delivery of this potentially therapeutic CNTF agent to the retina. The blood-retinal barrier prevents or inhibits the penetration of macro-molecules to the neurosensory retina, similar to the action of the blood-brain barrier in limiting transfer between the systemic circulation and the central nervous system. To address this issue, Neurotech USA, Inc., developed encapsulated cell technology (ECT) to provide controlled, sustained delivery of therapeutic agents directly into the intraocular fluids and thereby providing direct access to the retina. Cells within the ECT device are transfected with the CNTF gene and produce CNTF protein which exits through a semi-permeable polymer capsule membrane directly into the vitreous. The Neurotech NT-501 ECT device measures approximately 1mm x 6 mm and can readily be retrieved from the eye, providing an added level of safety. The previous Phase 1 and Phase 2 studies in RP and AMD have clearly demonstrated that CNTF is released by the implanted device and have also demonstrated that CNTF reaches and modifies the retina. Human clinical trials are being conducted to explore the safety and efficacy of these CNTF ocular implants on retinal structure and function in 5 patients with acromatopsia due to CNGB3 mutations(see below). To further explore the efficacy of CNTF in achromatopsia, we have delivered CNTF by intravitreal injection to the mouse model, which has a deletion of the CNGB3 gene. The model shows a severe and early reduction in cone function, while maintaining relatively good rod function as measured by the electrotretinogram (ERG). We previously showed that intravitreal injection of CNTF into normal rat eye suppresses rod function by down-regulating molecular mechanisms involved in converting light to visual signals (phototransduction). However, as mentioned above, it protects photoreceptors in several inherited and light induced models of retinal degeneration. Recently, it was shown that CNTF also protects cones from degeneration in one of these models, and actually partially restores the functional organelle for light reception, the cone outer segment. This indicates the possible anatomical basis for the recovery of cone function in humans and and CNGB3 dogs mentioned above. Using the CNGB3 mouse model of achromatopsia we showed that CNTF produces a small but significant increase in cone sensitivity indicating a possible therapeutic benefit. A 5 subject open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/day) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for one year. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold or the photopic ERG. This reveals a species difference between human and canine CNGB3 cones in responses to CNTF. Clinical protocol: CNTF Implants for CNGB3 Achromatopsia identifier: NCT01648452 Objective: The objective of this study is to evaluate the safety of ocular NT-501 device with encapsulated NT-201 cells releasing Ciliary Neurotrophic Factor (CNTF) to the retina of participants affected with CNGB3 achromatopsia. Study Population: Five participants affected with CNGB3 achromatopsia are enrolled, with one eye treated per participant. Design: This is a Phase I/II, prospective, single-center study. One eye of each participant received a vitreous NT-501 device implant releasing CNTF. The study will be completed once the final participant has received three years of follow-up. Outcome Measures: The primary outcome is the number and severity of adverse events and systemic and ocular toxicities at six months post-implantation. Additional safety of ocular CNTF implants in participants with CNGB3 achromatopsia will be determined from assessment of retinal function, ocular structure and occurrence of adverse events at all time points. Secondary outcomes include changes in visual function including visual acuity and color vision, electroretinogram (ERG) responses, and retinal imaging with optical coherence tomography (OCT).

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Li, David; Jin, Chongfei; Jiao, Xiaodong et al. (2014) AIPL1 implicated in the pathogenesis of two cases of autosomal recessive retinal degeneration. Mol Vis 20:1-14
Song, Hongman; Bush, Ronald A; Vijayasarathy, Camasamudram et al. (2014) Transgenic expression of constitutively active RAC1 disrupts mouse rod morphogenesis. Invest Ophthalmol Vis Sci 55:2659-68
Zein, Wadih M; Jeffrey, Brett G; Wiley, Henry E et al. (2014) CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci 55:6301-8
Huynh, Nancy; Jeffrey, Brett G; Turriff, Amy et al. (2014) Sorting out co-occurrence of rare monogenic retinopathies: Stargardt disease co-existing with congenital stationary night blindness. Ophthalmic Genet 35:51-6
Marangoni, Dario; Wu, Zhijian; Wiley, Henry E et al. (2014) Preclinical Safety Evaluation of a Recombinant AAV8 Vector for X-linked Retinoschisis after Intravitreal Administration in Rabbits. Hum Gene Ther Clin Dev :
Ziccardi, Lucia; Vijayasarathy, Camasamudram; Bush, Ronald A et al. (2014) Photoreceptor pathology in the X-linked retinoschisis (XLRS) mouse results in delayed rod maturation and impaired light driven transducin translocation. Adv Exp Med Biol 801:559-66
Swaroop, A; Sieving, P A (2013) The golden era of ocular disease gene discovery: race to the finish. Clin Genet 84:99-101
Sergeev, Yuri V; Vitale, Susan; Sieving, Paul A et al. (2013) Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes. Hum Mol Genet 22:4756-67
D'Souza, Leera; Cukras, Catherine; Antolik, Christian et al. (2013) Characterization of novel RS1 exonic deletions in juvenile X-linked retinoschisis. Mol Vis 19:2209-16
Bowne, Sara J; Sullivan, Lori S; Avery, Cheryl E et al. (2013) Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa. Mol Vis 19:2407-17

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