Centro Andaluz de Biología Molecular y Medicina Regenerativa

Retinal degeneration: from genetics to therapy

/Research Groups/Retinal degeneration: from genetics to therapy

Research lines:

Degenerative diseases of the retina are a heterogeneous group of ophthalmological pathologies, which are produced by the degeneration of photoreceptors and/or retinal pigment epithelium, with the consequent progressive loss of visual acuity leading to blindness. According to statistics published by the World Health Organization (WHO), it is estimated that at least 2.2 billion people have visual impairment or blindness, of which at least 1 billion have a visual impairment that could have been prevented or even treated. With the recent development of advanced therapies in ophthalmic clinical practice, some cases of retinal degeneration, which were previously incurable, are currently being treated. For this reason, more research is needed to continue the worldwide fight against blindness.

Our research focuses on inherited monogenic retinal dystrophies such as retinitis pigmentosa (RP) and genetically complex diseases affecting vision like age-related macular degeneration (AMD). Starting from the genetic information, we pursue the study of specific disease mechanisms to explore and test new therapeutics for degenerative retinopathies that are currently incurable. To study the molecular mechanisms of retinal degeneration, we used both classical in vivo models of retinal degeneration and cellular models by reprogramming induced pluripotent stem (iPS) cells obtained from clinical samples and their subsequent differentiation into specific cell types of the retina. All our experimental tools and human resources are ultimately focused on translational research since the final goal of our research project is the development and preclinical evaluation of new therapies to treat retinal degenerative diseases. Our approach includes gene therapy and gene editing using CRISPR/Cas9 technology, cell therapy using iPS, development of new neuroprotective small molecules as well as the application of nanotechnology and biomaterials for therapeutic purposes. In the frame of translational research, we have created the Spin-off Limno Pharma S.L. to boost a future clinical trial for RP and AMD. We also work in close collaboration with the Clinical Ophthalmology Department of University Hospital Virgen Macarena and patient’s associations.

The main research lines of the group are:

i) Functional characterization of genes related to eye disease.
ii) Impact of mutations on protein function to understand the molecular basis of the disease.
iii)Development of novel therapeutic approaches and biomarkers for retinal degenerative diseases.

Current research projects:

  • Preclinical study to evaluate the safety and efficacy of retinal pigment epithelium transplants grown on a nanostructured hydrogel to treat age-related macular degeneration (AMD CELLS-II). PI20/00043
  • Preclinical study of ex vivo genomic editing therapy for retinitis pigmentosa. PI-0099-2018
  • Preclinical study to evaluate SIRT1 and VEGF modulating drugs as a therapeutic for macular degeneration and diabetic retinopathy (SIRT-IN-EYES). PI17/01026

Predoctoral and Master’s students are welcome to join our research lines.

Recent Funding:

Scientific production (last 5 years)

  1. Ajana S, Cougnard-Grégoire A, Colijn JM, Merle BM, Verzijden T, de Jong PT, Hofman A, Vingerling JR, Hejblum BP, Korobelnik JF, Meester-Smoor MA, Ueffing M, Jacqmin-Gadda H, Klaver CC, Delcourt C; EYE-RISK Consortium. Predicting progression to advanced age-related macular degeneration from clinical, genetic and lifestyle factors using machine learning. Ophthalmology. 2020 Sep 2:S0161-6420(20)30849-6. doi: 10.1016/j.ophtha.2020.08.031. PMID: 32890546
  2. Acar İE, Lores-Motta L, Colijn JM, Meester-Smoor MA, Verzijden T, Cougnard-Gregoire A, Ajana S, Merle BMJ, de Breuk A, Heesterbeek TJ, van den Akker E, Daha MR, Claes B, Pauleikhoff D, Hense HW, van Duijn CM, Fauser S, Hoyng CB, Delcourt C, Klaver CCW, Galesloot TE, den Hollander AI; EYE-RISK Consortium. Integrating metabolomics, genomics and disease pathways in age-related macular degeneration: The EYE-RISK Consortium. Ophthalmology. 2020 Jun 14:S0161-6420(20)30561-3. doi: 10.1016/j.ophtha.2020.06.020. PMID: 32553749
  3. Biarnés M, Colijn JM, Sousa J, Ferraro LL, Garcia M, Verzijden T, Meester-Smoor MA, Delcourt C, Klaver CCW, den Hollander AI, Lengyel I, Peto T, Monés J; EYE-RISK Consortium Genotype- and Phenotype-Based Subgroups in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The EYE-RISK Consortium. Ophthalmol Retina. 2020 May 1:S2468-6530(20)30167-6. doi: 10.1016/j.oret.2020.04.014. Online ahead of print.PMID: 32371126
  4. Valdés-Sánchez L, Calado SM, De la Cerda B, Aramburu A, García-Delgado AB, Massalini S, Montero-Sánchez A, Bhatia V, Rodríguez-Bocanegra E, Diez-Lloret A, Rodríguez-Martínez D, Chakarova C, Bhattacharya SS, Díaz-Corrales FJ. Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins. Mol Med, 2019. Dec 31;26(1). doi: 10.1186/s10020-019-0124-z
  5. Garcia-Delgado AB, Calado SM, Valdes-Sanchez LM, Montero-Sanchez A, Ponte-Zuñiga B, De la Cerda B, Bhattacharya SS, Diaz-Corrales FJ. Generation of a human iPS cell line (CABi003-A) from a patient with age-related macular degeneration carrying the CFH Y402H polymorphism. Stem Cell Res, 2019. doi: 10.1016/j.scr.2019.101473. 38:101473.
  6. De la Cerda B, García Delgado AB, Alba Amador J, Valdés Sánchez ML, Fernández-Muñoz B, Relimpio López I, Rodríguez de la Rúa E, Díez Lloret A, Calado SM, Sánchez Pernaute R, Bhattacharya SS, Díaz Corrales FJ. Subretinal Transplant of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium on Nanostructured Fibrin-Agarose. Tissue Eng Part A, 25(9-10) 799-808. 2019. doi: 10.1089/ten.TEA.2019.0007.
  7. De la Cerda B, Díez-Lloret A, Ponte B, Vallés-Saiz L, Calado SM, Rodríguez E, Garcia-Delgado AB, Moya-Molina M, Bhattacharya SS, Díaz-Corrales FJ. Generation and characterization of the human iPSC line CABi001-A from a patient with retinitis pigmentosa caused by a novel mutation in PRPF31 gene. Stem Cell Res, 2019. doi: 10.1016/j.scr.2019.101426. 36:101426.
  8. Cabello M, Mozo M, De la Cerda B, Aracil C, Diaz-Corrales FJ, Perdigones F, Valdes-Sanchez L, Relimpio I, Bhattacharya SS, Quero JM. Gold microelectrodes array embedded in PDMS for electrical stimulation and signal detection. Sensors and Actuators B: Chemical, 228: 337-346. 2019. doi.org/10.1016/j.snb.2019.02.118 228, 337-346.
  9. Kersten E, Dammeier S, Ajana S, Groenewoud JMM, Codrea M, Klose F, Lechanteur YT, Fauser S, Ueffing M, Delcourt C, Hoyng CB, de Jong EK, den Hollander AI; EYE-RISK Consortium. Metabolomics in serum of patients with non-advanced age-related macular degeneration reveals aberrations in the glutamine pathway. PLoS One, 0218457, 14(6). 2019. doi: 10.1371/journal.pone.
  10. Merle BMJ, Colijn JM, Cougnard-Grégoire A, de Koning-Backus APM, Delyfer MN, Kiefte-de Jong JC, Meester-Smoor M, Féart C, Verzijden T, Samieri C, Franco OH, Korobelnik JF, Klaver CCW, Delcourt C; EYE-RISK Consortium. Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration: The EYE-RISK Consortium. Ophthalmology 2019. e0218457. doi: 10.1016/j.ophtha.2018.08.006.14(6).
  11. Colijn JM, den Hollander AI, Demirkan A, Cougnard-Grégoire A, Verzijden T, Kersten E, Meester-Smoor MA, Merle BMJ, Papageorgiou G, Ahmad S, Mulder MT, Costa MA, Benlian P, Bertelsen G, Bron AM, Claes B, Creuzot-Garcher C, Erke MG, Fauser S, Foster PJ, Hammond CJ, Hense HW, Hoyng CB, Khawaja AP, Korobelnik JF, Piermarocchi S, Segato T, Silva R, Souied EH, Williams KM, van Duijn CM, Delcourt C, Klaver CCW; European Eye Epidemiology Consortium; EYE-RISK Consortium. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration: Evidence from the EYE-RISK and European Eye Epidemiology Consortia. Ophthalmology 126(3): 393-406. 2019. doi: 10.1016/j.ophtha.2018.09.045.
  12. Calado SM, Garcia-Delgado AB, De la Cerda B, Ponte-Zuñiga B, Bhattacharya SS, Díaz-Corrales FJ. Generation of a human iPS cell line from a patient with retinitis pigmentosa due to EYS mutation. Stem Cell Res 33 251-254. 2018 doi: 10.1016/j.scr.2018.11.002.
  13. Rose AM, Krishan A, Chakarova CF, Moya L, Chambers SK, Hollands M, Illingworth JC, Williams SMG, McCabe HE, Shah AZ, Palmer CNA, Chakravarti A, Berg JN, Batra J, Bhattacharya SS. MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer. Ann Oncol. 2018 May 1;29(5):1292-1303. doi: 10.1093/annonc/mdy082.
  14. Alfano G, Waseem NH, Webster AR, Bhattacharya SS. Identification and characterization of the VAX2 p. Leu139Arg variant: possible involvement of VAX2 in cone dystrophy. Ophthalmic Genet. 2018 Aug;39(4):539-543. doi: 10.1080/13816810.2018.1484927.
  15. Brown CN, Green BD, Thompson RB, den Hollander AI, Lengyel I; EYE-RISK consortium. Metabolomics and Age-Related Macular Degeneration. Metabolites. 9(1): pii: E4: 2018. doi: 10.3390/metabo9010004
  16. García-Delgado AB, Valdés-Sánchez L, Calado SM, Diaz-Corrales FJ, Bhattacharya SS. Rasagiline delays retinal degeneration in a mouse model of retinitis pigmentosa via modulation of Bax/Bcl-2 expression. CNS Neurosci Ther 24(5), 448-455. 2018. doi: 10.1111/cns.12805.
  17. Miguel Cabello; Carmen Aracil, Francisco Perdigones, Marta Mozo, Berta de la Cerda, José M. Quero. Gold microelectrodes array embedded in PDMS for electrical stimulation and signal detection. Sensors and Actuators B: Chemical, 257, 954-962. 2017
  18. Mladenova K, Petrova SD, Andreeva TD, Moskova-Doumanova V, Topouzova-Hristova T, Kalvachev Y, Balashev K, Bhattacharya SS, Chakarova C, Lalchev Z, Doumanov JA. Effects of Ca2+ ions on bestrophin-1 surface films. Colloids Surf B Biointerfaces. 2017 Jan 1;149: 226-232. doi: 10.1016/j.colsurfb.2016.10.023. PMID: 27768912
  19. Rose AM, Luo R, Radia UK, Bhattacharya SS. Gene of the month: PRPF31. J Clin Pathol. 2017 Sep;70(9):729-732. doi: 10.1136/jclinpath-2016-203971. Epub 2017 Jun 29. Review. PMID: 28663330
  20. Colijn JM, Buitendijk GHS, Prokofyeva E, Alves D, Cachulo ML, Khawaja AP, Cougnard-Gregoire A, Merle BMJ, Korb C, Erke MG, Bron A, Anastasopoulos E, Meester-Smoor MA, Segato T, Piermarocchi S, de Jong PTVM, Vingerling JR, Topouzis F, Creuzot-Garcher C, Bertelsen G, Pfeiffer N, Fletcher AE, Foster PJ, Silva R, Korobelnik JF, Delcourt C, Klaver CCW; EYE-RISK consortium; European Eye Epidemiology (E3) consortium. Prevalence of Age-Related Macular Degeneration in Europe. The Past and the Future. 2017 Ophthalmology, 14,12, 1753-1763.
  21. Mladenova K, Petrova SD, Andreeva TD, Moskova-Doumanova V, Topouzova-Hristova T, Kalvachev Y, Balashev K, Bhattacharya SS, Chakarova C, et al. Effects of Ca2+ ions on bestrophin-1 surface films. Colloids and Surfaces B: Biointerfaces, 149: 226-232.
  22. Calado SM, Diaz-Corrales FJ, Silva GA. pEPito-driven PEDF Expression Ameliorates Diabetic Retinopathy Hallmarks. Human Gene Therapy Methods, 27: 79-86. 2016
  23. Pensado A, Diaz-Corrales FJ, De la Cerda B,Valdés-Sánchez L, Del Boz AA, Rodriguez-Martinez D, García-Delgado AB, Seijo B, Bhattacharya SS, Sanchez A. Span Poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa. Nanomedicine, (8): 2251-2260. 2016
  24. Czub B, Shah AZ, Alfano G, Kruczek PM, Chakarova CF, Bhattacharya SS. 2016. TOPORS, a Dual E3 Ubiquitin and Sumo1 Ligase, interacts with 26 S Protease Regulatory Subunit 4, Encoded by the PSMC1 Gene. PLoS One. 11(2).
  25. Dopazo J, Amadoz A, Bleda M, Garcia-Alonso L, Alemán A, García-García F, Rodriguez JA, Daub JT, Muntané G, Rueda A, Vela-Boza A, López-Domingo FJ, Florido JP, Arce P, Ruiz-Ferrer M, Méndez-Vidal C, Arnold TE, Spleiss O, Alvarez-Tejado M, Navarro A, Bhattacharya SS, BorregoS, Santoyo-López J, Antiñolo G. 2016. 267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation. Mol Biol Evol. 33(5):1205-18.

Patents

  1. Berta De la Cerda Haynes; Francisco Javier Díaz Corrales; Ana Belén García Delgado; Aránzazu Díaz Cuenca; Sara Borrego González. COMPOSICIÓN BIOPOLIMÉRICA, PROCEDIMIENTO PARA SU PREPARACIÓN Y USO DE LA MISMA. Application number: ES1641.1483. Priority: Spain. Registration Date: 05-11-2019. Applicants: Fundación Pública Andaluza Progreso y Salud, CSIC.
  2. Juan Carlos Morales, F. Javier Díaz Corrales, Lourdes Valdés, Ana Belén García Delgado, Adoración Montero. COMPUESTOS ACILADOS PARA EL TRATAMIENTO DE PATOLOGÍAS OCULARES. Application number: ES1641.1252 (WO2018096196A1). Priority: Spain. Registration Date: 23-11-2016. Applicants: Fundación Pública Andaluza Progreso y Salud, CSIC.
  3. Francisco Díaz Corrales; Berta De La Cerda; Lourdes Valdés; Shomi Bhattacharya; Andrea Pensado; Begoña Siego; Alejandro Sánchez. NANOPARTICULATE SYSTEMS FOR USE IN GENE TRANSFER OR GENE DELIVERY. Application number: EP14382221.1 (WO2015189429). Priority: Spain. Registration Date: 17-12-2015. Applicants: Fundación Pública Andaluza Progreso y Salud, Universidad de Santiago de Compostela.

Group leader:
  • Dr. Francisco J. Díaz Corrales
Senior Researchers:
  • Dr. Berta De La Cerda Haynes
Postdoctorals:
  • Dr. Estefania Caballano Infantes
  • Dr. Álvaro Plaza Reyes
Visiting scientists:
  • Shunei Mitani
PhD students:
  • Mohamad Mehdi Moshtaghion
Technicians:
  • Marta Torres Valcárcel
  • Dr. Lourdes Valdés Sánchez
  • Adoración Montero Sánchez