Perspectivas Farmacológicas de Futuro en el Tratamiento de la Degeneración Macular Relacionada a la Edad (DMRE) Neovascular. Parte 2: Terapia Génica y Fármacos en Estudios Pre Clínicos.

Miguel Rodriguez Guanare

Resumen


Objetivos: Presentar una revisión acerca de la terapia génica y los fármacos en estudios preclínicos como nuevos y posibles blancos de tratamiento farmacológicos para la degeneración macular relacionada a la edad neovascular y el estado de los estudios clínicos de los mismos.
Diseño del estudio: Revisión de tema
Métodos: Se realizó una búsqueda de la literatura electrónica disponible en EMBASE, PUBMED y Google Scholar acerca del tema y se complementa con la información encontrada en www.clinicaltrials.gov y la plataforma de registros internacionales de ensayos clínicos de la OMS.

Conclusiones: La terapia génica vinculada a la degeneración macular asociada a la edad neovascular muestra un avance científico importante en el campo de la farmacología ocular pudiendo proporcionar efi cacia tras una sola inyección de un vector que puede expresar continuamente una proteína elegida. Existen estudios pre-clínicos que sugieren nuevos y diversos blancos farmacológicos para la degeneración macular relacionada a la edad mostrando un perfi l de seguridad y efi cacia signifi cativo.




Palabras clave


Degeneración macular relacionada a la edad (DMRE) neovascular, factor de crecimiento endotelial vascular (VEGF), terapia génica.

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Referencias


Reynolds AL, Kent D, Kennedy BN. Retinal Degenerative Diseases. Ash JD, Grimm C, Hollyfi eld JG, Anderson RE, LaVail MM, Bowes Rickman C, editors. New York, NY: Springer New York; 2014;801:797–804. 2. Binley K, Widdowson PS, Kelleher M, de Belin J, Loader J, Ferrige G, et al. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(®), for age-related macular degeneration. Hum Gene Th er 2012;23:980–91. 3. Philippidis A. Gene therapy briefs. Hum Gene Th er 2014;25:12–6. 4. Van Vliet KM, Blouin V, Brument N, Agbandje

McKenna M, Snyder RO. The role of the adenoassociated virus capsid in gene transfer. Methods Mol Biol. 2008;437:51–91. 5. Mueller C, Flotte TR. Clinical gene therapy using recombinant adeno-associated virus vectors. Gene Th er. 2008;15:858–63. 6. Maclachlan TK, Lukason M, Collins M, Munger R, Isenberger E, Rogers C, et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther; 2011;19:326–34. 7. Pechan P, Rubin H, Lukason M, Ardinger J, Dufresne E, Hauswirth WW, et al. Novel anti

Revista VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization. Gene Th erapy 2009;1:10–6. 8. Rasmussen H, Chu KW, Campochiaro P, Gehlbach PL, Haller JA, Handa JT, et al. Clinical protocol. An open-label, phase I, single administration, doseescalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum Gene Th er 2001;12:2029-32. 9. Nakamura T, Nawa K, Ichihara A. Partial purifi cation and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 1984;122:1450–9. 10. Russell WE, McGowan JA, Bucher NL. Partial characterization of a hepatocyte growth factor from rat platelets. J Cell Physiol 1984;119:183–92. 11. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. Identifi cation of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251:802–4. 12. Tamagnone L, Comoglio PM. Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors. Cytokine and Growth Factor Reviews 1997. p. 129–42. 13. Nakamura Y, Morishita R, Higaki J, et al. Hepatocyte growth factor is a novel member of the endotheliumspecifi c growth factors: additive stimulatory eff ect of hepatocyte growth factor with basic fi broblast growth factor but not with vascular endothelial growth factor. J Hypertens 1996;14:1067e72. 14. Cao B, Su Y, Oskarsson M, et al. Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc Natl Acad Sci U S A 2001;98:7443e8 15. Anand A, Sharma NK, Singh R, Gupta A, Prabhakar S, Jindal N, et al. Does DcR1 (TNFrelated apoptosis-inducing-ligand Receptor 3) have any role in human AMD pathogenesis? Sci Rep 2014;4:4114. 16. Wu X, Lippman SM. An intermittent approach for cancer chemoprevention. Nat Rev Cancer 2011;11:879–85. 17. Zhou Q, Anderson C, Zhang H, Li X, Inglis F, Jayagopal A, et al. Repression of choroidal neovascularization through actin cytoskeleton pathways by microRNA-24. Mol Ther 2014;22:378–89. 18. Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin fi laments. Cell 2003;112:453–65.

Hall a. Rho GTPases and the actin cytoskeleton. Science 1998;279:509–14. 20. Fryer BH, Field J. Rho, Rac, Pak and angiogenesis: old roles and newly identifi ed responsibilities in endothelial cells. Cancer Lett 2005;229:13–23. 21. Park H-J. 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA. Circ Res 2002;91:143–50. 22. Hoang M V, Whelan MC, Senger DR. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc Natl Acad Sci U S A 2004;101:1874–9. 23. Liu B, Novick D, Kim SH, Rubinstein M. Production of a biologically active human interleukin 18 requires its prior synthesis as PRO-IL-18. Cytokine 2000;12:1519–25. 24. Ushio S, Okura T, Hattori K, Nukada Y, Akita K, Tanabe F, et al. Cloning of the cDNA for Human IFN-y-Inducing Factor, Expression in E Coli. J Immunol 1996;156;4274-9. 25. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. Th e NALP3 infl ammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 2008;9:857–65. 26. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 infl ammasome activation. Nature 2011;469:221–5. 27. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the infl ammasome in response to toxins and ATP. Nature 2006;440:228–32. 28. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 infl ammasome. Nature 2006;440:237–41. 29. Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 2012;18:791–8. 30. Gao H, Hollyfield JG. Aging of the human retina. Diff erential loss of neurons and retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 1992;33:1–17. 31. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile infl ammatory response through the Nlrp3 infl ammasome. Proc Natl Acad Sci U S A 2009 ;106:2088–93. 32. Hollyfi eld JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, et al. Oxidative damageinduced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194–8. 33. Gu X, Meer SG, Miyagi M, Rayborn ME, Hollyfi eld JG, Crabb JW, et al. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem 2003;278:42027–35. 34. Campbell M, Humphries MM, Kiang A-S, Nguyen ATH, Gobbo OL, Tam LCS, et al. Systemic lowmolecular weight drug delivery to pre-selected neuronal regions. EMBO Mol Med 2011;3:235–45. 35. Sakurai E. Macrophage Depletion Inhibits Experimental Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2003;44:3578–85. 36. Doyle SL, Ozaki E, Brennan K, Humphries MM, Mulfaul K, Keaney J, et al. IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Sci Transl Med 2014 ;6:230ra44. 37. Oltean S, Gammons M, Hulse R, HDMREollahZadeh M, Mavrou A, Donaldson L, et al. SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases. Biochem Soc Trans 2012;40(4):831–5.

Gammons M V, Fedorov O, Ivison D, Du C, Clark T, Hopkins C, et al. Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative DMRE. Invest Ophthalmol Vis Sci 2013;54:6052–62. 39. Cloutier F, Lawrence M, Goody R, Lamoureux S, Al-Mahmood S, Colin S, et al. Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration. Invest Ophthalmol Vis Sci 2012;53:1195–203. 40. Gerritsen ME. HGF and VEGF: a dynamic duo. Circ Res 2005;96:272e3 41. Nishimura M, Ikeda T, Ushiyama M, et al. Increased vitreous concentrations of human hepatocyte growth factor in proliferative diabetic retinopathy. J Clin Endocrinol Metab 1999;84:659e62. 42. Hu W, Criswell MH, Fong SL, et al. Diff erences in the temporal expression of regulatory growth factors during choroidal neovascular development. Exp Eye Res 2009;88:79e91 43. Zhou Q, Anderson C, Zhang H, Li X, Inglis F, Jayagopal A, et al. Repression of choroidal neovascularization through actin cytoskeleton pathways by microRNA-24. Mol Ther 2014;22:378–89.


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