The ultimate goal of this research is to lay the foundation for the application of cell therapy in the treatment of retinal dystrophies, by implanting healthy cells, obtained from iPS cells, in the patients' affected tissues.
Fundació Bancària “La Caixa”
IMO Foundation's own funds
November 2017 - present
The first objective of this research project is to obtain a study model for retinal dystrophies, a heterogeneous group of congenital pathologies that constitute the first cause of hereditary blindness in developed countries. To this end, the aim is to obtain induced pluripotent stem cells (iPSCs) from skin biopsies of the affected patients, which will subsequently be reprogrammed into retinal cells such as photoreceptors. These cells will allow the functional study of some of the mutations that cause retinal dystrophies, as well as the analysis of the effectiveness of new tools for the treatment of this type of pathology.
Therapeutic testing using these cells is the second objective of the project, which consists of the "in vitro" correction of the altered genes using the revolutionary new CRISPR-Cas9 gene therapy technology. Thus, if the results in the laboratory show that the methodology corrects the mutations and that it is also safe to stop the loss of vision, the door will be opened to its future application in patients.
Ultimately, the results of this research study will lay the foundation for the application of cell therapy in hereditary retinal diseases, through the implantation of healthy cells in the patient's affected tissues. In this way, while gene therapy aims to stop the loss of vision, cell therapy will in the future allow the recovery of the patient's visual function.
Current status of the project
The results obtained by the end of 2019, made possible the generation of 7 new iPS cell lines from skin samples of 7 patients affected by different types of retinal dystrophies, including Stargardt's Disease and Retinitis Pigmentosa. In addition, these cellular models were characterized and published in high impact international scientific journals.
These stem cells, with the ability to transform into almost any cell in the body (pluripotent cells), differentiated into the two main cell types of the retina: photoreceptors and retinal pigment epithelium (RPE) cells.
Currently, we are also working on a long-term protocol, approximately 9 months, with which it is intended to generate 3D cultures, also called organoids, to generate retinas in culture from the stem cells derived from the 7 patients. These organoids more precisely mimic the retina of our patients and, therefore, the functional defects that it presents. The three models studied (photoreceptors, EPR and organoids) are allowing us to determine in depth the cellular and molecular causes of retinal dystrophies and also study their possible use in gene and cell therapy.On the other hand, we are trying to correct the genetic variants described in patients in the different iPS lines, a process known as gene editing. We do this through various technologies based on genetic engineering such as CRISPR/Cas9 or TALENs. We are currently working and using new designs to try to optimize the process. The ultimate goal of gene editing is to be able to repair genetic alterations in vitro and to be able to reverse the pathology in the patient's cultured cells, so that later they can be used as a therapeutic treatment.
Related research papers
Riera M, Patel A, Corcostegui B, Chang S, Sparrow JR, Pomares E, Corneo B. Establishment and characterization of an iPSC line (FRIMOi001-A) derived from a retinitis pigmentosa patient carrying PDE6A mutations. Stem Cell Res. 2019 Mar;35:101385.
Riera M, Patel A, Corcostegui B, Chang S, Corneo B, Sparrow JR, Pomares E. Generation of an induced pluripotent stem cell line (FRIMOi002-A) from a retinitis pigmentosa patient carrying compound heterozygous mutations in USH2A gene. Stem Cell Res. 2019 Mar;35:101386.
Riera M, Patel A, Burés-Jelstrup A, Corcostegui B, Chang S, Pomares E, Corneo B, Sparrow JR. Generation of two iPS cell lines (FRIMOi003-A and FRIMOi004-A) derived from Stargardt patients carrying ABCA4 compound heterozygous mutations. Stem Cell Res. 2019 Apr;36:101389.
Domingo-Prim J, Riera M, Burés-Jelstrup A, Corcostegui B, Pomares E. Establishment of an induced pluripotent stem cell line (FRIMOi005-A) derived from a retinitis pigmentosa patient carrying a dominant mutation in RHO gene. Stem Cell Res. 2019 Jul;38:101468.
Domingo-Prim J, Riera M, Abad-Morales V, Ruiz-Nogales S, Corcostegui B, Pomares E. Generation of Best disease-derived induced pluripotent stem cell line (FRIMOi006-A) carrying a novel dominant mutation in BEST1 gene. Stem Cell Res. 2019 Oct;40:101570.
Domingo-Prim J, Abad-Morales V, Riera M, Navarro R, Corcostegui B, Pomares E. Generation of an induced pluripotent stem cell line (FRIMOi007-A) derived from an incomplete achromatopsia patient carrying a novel homozygous mutation in PDE6C gene. Stem Cell Res. 2019 Oct;40:101569.