NanoCrisprAlbino Therapy. Preclinical development of CRISPR-based non-viral therapeutic approaches in existing cellular and animal models of Albinism.

Principal investigator from CIBER BBN: Jose Luis Pedraz and principal investigator from CIBERER: LLuís Montoliu, Gustavo Puras, Ilia Villate, Jesus Ciriza y Laura Saenz del Burgo.
from 2017 to 2019
Financing entity:
CIBER BBN/Instituto de Salud Carlos III
Total amount:

Albinism is a human rare genetic condition associated with mutations in at least 20 genes. In Europe, the estimated frequency of albinism is approximately 1:17,000 newborn. Albinism is associated with a diagnostic severely impaired vision, featuring limited visual acuity (often <0.1) due to foveal hypoplasia and, lack of stereoscopic vision, due to abnormal retinal nerve connections with the brain nuclei processing the visual information. Albinism can also include hypopigmentation in skin, hair and eyes, or only eyes. The commonest form of non-syndromic oculo-cutaneous albinism (OCA) is OCA1, associated with mutations in the TYR gene. This Proposal aims to develop innovative pre-clinical therapeutic approaches in existing cellular and animal models of OCA1. Mutant mice and melanocytes for OCA1 research are already available to the consortium. In particular, we will assess albinism mutations in mice commonly found in the human population, as the T373K classical TYR mutation, whose counterpart in mice is the T373I Tyr extreme dilution mottled mutant allele (Tyr). We will apply the latest gene-editing techniques, CRISPR-Cas tools, for assessing the feasibility of in vitro and in vivo strategies for gene correction using specifically-designed non-viral delivery methods, capable of efficiently transferring the CRISPR-Cas ribonucleoprotein (RNP) complex and the template oligonucleotide DNA into the cells. We will make use of CRISPR reagents to restore the correct homologous murine Tyr gene mutated, and deliver it to cells and mice using a most innovative non-viral delivery system of lipid nanoparticles based on cationic niosomes. The combined expertise of the two complementary groups in mouse/human genetics, molecular biology, animal models, cellular biology, CRISPR gene-editing methods and non-viral gene-delivery systems make this proposal unique for investigating the translational potential of future therapeutic approaches for albinism, devised in mice and cells.