Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants

Abstract

Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10-15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.

Conflict of interest statement

Conflict of interest statement: W.T. is employed by Neurotech USA, which provided the CNTF encapsulated cell implants under a National Institutes of Health Clinical Trials Agreement.

Figures

Fig. 1.

Visual acuity (VA) changes of the study eyes and fellow control eyes of the 10 participants over the 6-month implant period grouped by lower-dose implants (Phase IA) and higher-dose implants (Phase IB). Letter acuity changes are relative to the preimplant baseline acuity (designated as zero) and are not the absolute baseline level. Three participants in Phase IA had no measurable acuity perception throughout the trial and remained at zero throughout. Time 0 is the baseline visit, explant was at week 24, and week 28 was the 1-month postremoval examination.

Fig. 2.

Histology in longitudinal section of a CNTF device after removal at 6 months from the study eye of a Phase-IB participant. Histology of a comparable device that was not implanted is shown for comparison. NTC-201 cells are evident at approximately equal density on the poly(ethylene terephthalate) yarn scaffold. No macrophages were found in any explanted device. Shown are 4-μm-thick sections embedded in glycol methacrylate and stained with hematoxylin and eosin. (Magnification, ×10.)

Fig. 3.

Ocular fundus photograph of CNTF trial participant 001 shows clinical features representative of all 10 participants who have peripheral retina pigmentary changes typical for retinitis pigmentosa plus a central yellowish region of atrophic macular degeneration that accounts for the reduced visual acuities.