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.clinical trial ͉ neurodegeneration ͉ retinitis pigmentosa ͉ photoreceptor ͉ macular degeneration R etinitis pigmentosa (RP) describes a set of neurodegenerative retinal diseases that cause the death of photoreceptor cells and lead to progressive vision loss and blindness. More than 39 genetic loci and genes have been implicated in monogenic forms of RP (1), underscoring the complexity of its pathogenic mechanisms. With the exception of vitamin A nutritional supplementation (2), no treatments have been shown to be effective across the range of these disorders. Regardless of the initial causative genetic defect, the end result is photoreceptor cell death. The multiplicity of mechanisms stimulated a search for therapeutic agents that are effective in slowing photoreceptor death regardless of the causative genetic mutation.Intervention studies have indicated the possibility of using neurotrophic factors as therapeutic agents for RP (3). Specifically, ciliary neurotrophic factor (CNTF) is effective at retarding retinal degeneration in at least 13 animal RP models, including rd-PDE6b mice (4, 5), rds-peripherin mice (4, 6-10), transgenic rats expressing P23H or S334ter mutant rhodopsin (7, 10), Rdy cats (11), rcd1-PDE6b dogs (7), rhodopsin-knockout mice (9), and rd͞rd mice, nr͞nr mice, and Q334ter rhodopsin transgenic mice (4).CNTF also appears effective for retarding cellular and functional losses in neurodegenerative diseases ...

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

“…They were only observed when CNTF was injected before the canine retina had reached full maturation. Therefore, although this may not be an issue for adult human patients treated with sustained release of CNTF (Sieving et al, 2006), peripheral retinal changes observed in normal adult rabbits (Bush et al, 2004), and the suggestion that endogenous secretion of CNTF may be the cause of cell proliferation in humans with mutations in the NR2E3 gene (Jacobson et al, 2004) warrants further investigation. Schematic of a retinal section showing the location of the sites S1, S2, and S3.…”

“…Because of the inability for CNTF to cross the blood-retina barrier following systemic administration, the necessity for sustained bioavailablity of the agent in the eye, and the ocular side-effects associated with bolus intravitreal injection, a longterm intraocular delivery system has been developed (Thanos et al, 2004). This encapsulated cell-based technology (ECT) allows for the continuous release of small quantities of CNTF into the vitreous, and was evaluated in experimental animal models (Tao et al, 2002;Bush et al, 2004), and more recently in Phase I clinical trial in humans (Sieving et al, 2006). Previous work has shown that CNTF delivered through intravitreal injections (Pearce-Kelling, unpublished study), or by means of an ECT device (Tao et al, 2002), rescues photoreceptors in the rcd1 dog, an early and rapidly progressing large animal model of RP caused by a stop mutation in PDE6B.…”

Optogenetic therapy for retinitis pigmentosa

“…A second approach is to slow the degeneration of photoreceptors and thus slow progression of the disease. [13][14][15][16][17][18] Finally, there are a number of approaches that do not interfere with the intrinsic progression of disease but attempt to restore photosensitivity by creating new photosensors and coupling them to the remaining retinal circuitry. Patients who are legally blind are the key target population of these therapies.…”

The Neuroprotective Agent CNTF Decreases Neuronal Metabolites in the Rat Striatum: An in Vivo Multimodal Magnetic Resonance Imaging Study

“…1,2 It has been tested in clinical trials for Huntington's disease, 3 amyotrophic lateral sclerosis, 4 and diseases of the retina. 5 However, the mechanisms involved in CNTF neuroprotection remain largely uncharacterized.…”