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Ciliary Neurotrophic Factor in the Treatment of Advanced Nonexudative Age-Related Macular Degeneration

 

Veeral S. Sheth, MD

Theodore K. Lin, MD

Daniel F. Kiernan, MD

Rama D. Jager, MD, FACS

 

doctorAlthough the use of intravitreal ranibizumab and bevacizumab have created a paradigm shift in the management of exudative age-related macular degeneration (AMD), the majority of patients with AMD have nonexudative disease which, in its advanced form, can often result in significant and progressive visual loss.1 Currently, there are several ongoing clinical trials evaluating various agents for the treatment of nonexudative AMD, including agents which help prevent retinal degeneration.

 

Research into neurotrophic factors and the role they may play in rescue from retinal degeneration has been discussed for several decades. The use of ciliary neurotrophic factor (CNTF) using encapsulated cell-based delivery is one of the latest advancements in this technology.2,3 CNTF is a member of the interleukin-6 family of cytokines, which help regulate the acute-phase response to injury and have known anti-inflammatory and neuronal regenerative effects.4 CNTF has been studied systemically in neurodegenerative diseases5,6 and CNTF receptors have been found on retinal ganglion cells, Mueller cells, photoreceptors and retinal pigment epithelial cells.7,8 When CNTF binds its receptors on rods and cones, it activates a cascade that has been implicated in neuroprotection after light-induced retinal injury.9 However, systemic CNTF administration has not resulted in significant intraocular penetration secondary to the blood-retina barrier.10 Consequently, direct intraocular delivery systems are being evaluated to determine the potential benefits of CNTF in the management of vitreoretinal disease.

 

In 2007, Paul Sieving of the National Eye Institute and others published the results of a phase 1 trial evaluating the safety of intraocular constant CNTF delivery via encapsulated cell technology (ECT) intraocular implantation.11 The ECT-CNTF implants (Neurotech Pharmaceuticals, USA) contain genetically modified human retinal pigment epithelial cells which constantly secrete a controlled amount of recombinant human CNTF through a semipermeable polymer outer membrane. The ECT-CNTF implants were surgically placed into the vitreous cavity for six months in ten patients with retinitis pigmentosa (RP). Visual acuity improved by 10 or more letters in three of seven eyes with RP for which visual acuity could be tracked by conventional reading charts, although the study was not powered to evaluate efficacy. One patient had a choroidal detachment which resolved with conservative management. The authors concluded that CNTF appeared to be safe for the human retina based on this phase 1 study.

 

A phase 2 study examining the use of ECT-CNTF at two different doses in AMD patients with geographic atrophy was initiated in 2007. The Phase 2 study (Clinicaltrials.gov # NCT00447954) was a multi-centered, randomized, double-masked, sham-controlled study of 51 subjects with advanced nonexudative AMD with geographic atrophy. Preliminary results indicate that ECT-CNTF slowed visual loss at 12 months, with 96.3% of treated patients losing fewer than 15 letters of visual acuity versus 75% of the patients in the sham-treatment group, although the results were not statistically significant (p=0.078). In addition, there appears to be a dose-dependent, statistically significant (p=0.001 and p=0.013 for high and low dose, respectively) increase in retinal thickness as measured by optical coherence tomography. Unlike the phase 1 study, there were no serious adverse events observed in the phase 2 study.12

 

Given the 50% projected increase in AMD by the year 2020, the importance of evaluating a broad range of therapies for both exudative and nonexudative AMD has become increasingly important.13 ECT-CNTF may offer patients with advanced AMD the ability to prevent visual loss. However, the potential risks of implantation need to be weighed against the benefit of slowing the rate of visual loss in patients with advanced nonexudative AMD. The need for effective medications to arrest the progression of, and potentially reverse, geographic atrophy is paramount. CNTF has proven to be an intriguing avenue of research thus far.

 

 

REFERENCES

    1. Jager RD, Mieler WF, Miller JW. Age-related Macular Degeneration. N Engl J Med 2008;358(24):2606-17.
    2. Johnson JE, Barde YA, Schwab M, Thoenen H. Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J Neurosci. 1986;6(10):3031-8.
    3. Tao W, Wen R, Goddard MB et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43(10):3292-8.
    4. Heinrich PC, Behrmann I, Haan S et al. Principles of interleukin (IL)-6 type cytokine signaling and its regulation. Bichem J 2003;374(1):1-20.
    5. Garcia de Yebenes J, Yebenes J, Mena MA. Neurotox Res 2000;2(2):115-37.
    6. Lundberg C, Bjorklund T, Carlsson T, et al. Applications of lentiviral vectors for biology and gene therapy of neurological disorders. Curr Gene Ther 2008;8(6):461-73.
    7. Peterson WM, Wang Q, Tzekova R, Wiegad SJ. Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia. J Neurosci 2000;20(11):4081-90.
    8. Fuhrmann S, Kirsch M, Heller S, et al. Differential regulation of ciliary neurotrophic factor receptor-alpha expression in all major neuronal cell classes during development of the chick retina. J Comp Neurol 1998;400(2):244-54.
    9. Valter K, Bisti S, Gargini C, et al. Time course of neurotrophic factor upregulation and retinal protection against light-induced damage after optic nerve section. Invest Ophthalmol Vis Sci 2005;46:1748-54.
    10. MacDonald IM, Sauve Y, Sieving PA. Preventing blindness in retinal disease: ciliary neurotrophic factor intraocular implants. Can J Ophthalmol 2007;42(3):399-402.
    11. Sieving PA, Caruso RC, Tao W et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase 1 trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA 2006;103(10):3896-901.
    12. http://www.neurotechusa.com/news_events/pr_2009-03-26.asp Positive Results from Neurotech's NT-501 Phase 2 Dry AMD (Geographic Atrophy) Study Demonstrate Proof of Concept. Accessed April 7, 2009.
    13. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-72. .

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Ingrid U. Scott, MD, MPH,  Editor

Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine

 

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