CNTF Implants for CNGB3 Achromatopsia

Background:

* Achromatopsia is an inherited condition that causes vision loss because cells in the retina do not work properly. It causes loss of acuity, sensitivity to light, and loss of color vision. There are no effective treatments for achromatopsia.
* Four genes currently are known to cause achromatopsia. One of these, the cyclic nucleotide-gated channel beta 3 (CNGB3) gene, is the cause in about 50 percent of people.
* CNTF is a natural chemical found in the body that promotes survival and function of nerve cells. CNTF has been shown to be effective in treating retinal disease in animals and can slow vision loss.
* CNTF has also been studied in over 250 people with retinal disease other than achromatopsia. In these studies, a CNTF implant was placed into the eye during a simple surgery. The implant releases CNTF inside the eye, near the retina. These studies suggested that a CNTF implant might help vision in some eye diseases.

Objectives:

* To learn whether a CNTF implant is safe for people with CNGB3 achromatopsia.
* To learn whether CNTF can improve visual acuity or color vision, and whether it may reduce sensitivity to light in people with CNGB3 achromatopsia.

Eligibility:

You may be able to take part in this study if you:

* Are at least 18 years old.
* Test positive for mutations in the CNGB3 gene and have no mutations in another achromatopsia gene.
* Have 20/100 vision or worse in at least one eye.
* Are not pregnant or nursing.

Design:

* To determine if you can take part, we will ask about your medical history and do a physical examination and an eye examination. Blood and urine samples will be taken.
* This study requires 11 visits to the National Eye Institute over 3 years.
* One visit will be for the implant surgery. The implant will be placed in one eye only.
* Study visits will take place 1 day after implant surgery, and again 1 week later and 1 month, 3 months, 6 months, 1 year, 1.5 years and 3 years later. These visits will help us evaluate the safety and benefit of the implant on your eye.
* At the 3 year visit, you can choose to keep the CNTF implant in your eye, or you can have us remove it.

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 will be enrolled, with one eye treated per participant.

Design: This is a Phase I/II, prospective, single-center study. One eye of each participant will receive 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).

Eligibility Criteria:
Inclusion Criteria:

To be eligible, the following inclusion criteria must be met, where applicable.

* Participant must be 18 years of age or older.
* Participant must carry two alleles for CNGB3 gene mutations and no cyclic nucleotide-gated channel alpha 3 (CNGA3) sequence variations as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
* Participant must understand and sign the protocol informed consent.
* Both female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or must agree to use contraception during the first six months following implantation. Acceptable forms of contraception include:hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation).

Exclusion Criteria:

A participant is not eligible if any of the following exclusion criteria are present.

* Participant has a history of other ocular disease likely to contribute significantly to visual loss (e.g., optic neuropathy, glaucoma, uveitis, or other retinal disease).
* Participant is judged by the investigator as not sufficiently healthy to safely undergo ophthalmic surgery.
* Participant is on anticoagulant therapy that cannot be safely stopped peri-operatively at the implant procedure. Patients on warfarin will always be excluded. Patients on aspirin will be asked to stop the medication at least seven days prior to the surgery (when not contraindicated by the underlying medical condition). The stoppage period for other anticoagulant medications is based on the best clinical judgment of the investigator surgeon and is variable depending on the patient's medical condition and the type of medication.
* Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma skin cancer) within the previous five years.
* Participant has received investigational treatment in another clinical study related to an ocular condition in the last six months.
* Participant is pregnant, lactating or planning to become pregnant in the first six months following implantation.

Study Eye Eligibility Criteria:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

Study Eye Inclusion Criteria:

The study eye must have a best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity letterscore of ≤ 53 (i.e., ≤ 20/100). The visual acuity from the first baseline visit (Baseline 1) will be used for eligibility determination in case of a change in visual acuity at the second baseline visit (Baseline 2).

Study Eye Exclusion Criteria:

* The study eye has a choroidal nevus or ocular neoplasm with potential risk for malignant transformation.
* The study eye is judged by the investigator, based on history or examination findings, as high-risk for retinal detachment, vitreous hemorrhage, infection, or uveitis.
* The study eye has lens, cornea, or other media opacities precluding adequate visualization and testing of the retina.
* The study eye has undergone intraocular surgery within 12 months prior to enrollment.

Study Eye Selection Criteria in Cases of Bilateral Disease:

* As this is a genetic condition that usually affects both eyes to a similar degree, if both eyes of a participant meet the study eye eligibility criteria and have comparable visual acuity, the study eye will be selected at the investigator's medical judgment after consultation with the participant.
* In case of an eye with lower visual acuity, that eye will be selected as the study eye.