Aida García-Torralba

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

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José C. Segovia

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Isabel Ojeda-Pérez

Hospital Universitario Fundación Jiménez Díaz

Sergio López-Manzaneda

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Virginia Nieto-Romero

Instituto de Salud Carlos III

Omaira Alberquilla

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Andrea Molinos-Vicente

Instituto de Salud Carlos III

Juan A. Bueren

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

María García‐Bravo

Universidad Autónoma de Madrid

Rebeca Sánchez‐Domínguez

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Emmanuel Olivier

Albert Einstein College of Medicine

Cooperative Institutions

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Centre for Biomedical Network Research on Rare Diseases

Hospital Universitario Fundación Jiménez Díaz

Universidad Autónoma de Madrid

Biomedical Research Networking Center on Neurodegenerative Diseases

Universitat de Barcelona

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Harvard University

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Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts

iScience (2024)

Virginia Nieto-Romero Aida García-Torralba Andrea Molinos-Vicente Francisco Moya Sandra Rodríguez

Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the

Primary hyperoxaluria

Overproduction

Reprogramming

10.1016/j.isci.2024.109530

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Citations (4)

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation

Experimental Neurology (2019)

Albert Giralt Verónica Brito Mónica Pardo Sara E. Rubio Lucile Marion‐Poll

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.

Neural Development

10.1016/j.expneurol.2019.113095

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Preclinical studies of efficacy thresholds and tolerability of a clinically ready lentiviral vector for pyruvate kinase deficiency treatment

Molecular Therapy — Methods & Clinical Development (2021)

Susana Navarro Oscar Quintana‐Bustamante Rebeca Sánchez‐Domínguez Sergio López-Manzaneda Isabel Ojeda-Pérez

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder caused by mutations in the PKLR gene. PKD is characterized by non-spherocytic hemolytic anemia of variable severity and may be fatal in some cases during early childhood. Although not considered the standard of care, allogeneic stem cell transplantation has been shown as a potentially curative treatment, limited by donor availability, toxicity, and incomplete engraftment. Preclinical studies were conducted to define conditions to enable consistent therapeutic reversal, which were based on our previous data on lentiviral gene therapy for PKD. Improvement of erythroid parameters was identified by the presence of 20%–30% healthy donor cells. A minimum vector copy number (VCN) of 0.2−0.3 was required to correct PKD when corrected cells were transplanted in a mouse model for PKD. Biodistribution and pharmacokinetics studies, with the aim of conducting a global gene therapy clinical trial for PKD patients (RP-L301-0119), demonstrated that genetically corrected cells do not confer additional side effects. Moreover, a clinically compatible transduction protocol with mobilized peripheral blood CD34⁺ cells was optimized, thus facilitating the efficient transduction on human cells capable of repopulating the hematopoiesis of immunodeficient mice. We established conditions for a curative lentiviral vector gene therapy protocol for PKD.

Tolerability

Pyruvate kinase deficiency

10.1016/j.omtm.2021.07.006

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In Vitro and In Vivo Genetic Disease Modeling via NHEJ-Precise Deletions Using CRISPR-Cas9

Molecular Therapy — Methods & Clinical Development (2020)

Sergio López-Manzaneda Isabel Ojeda-Pérez Nerea Zabaleta Aida García-Torralba Omaira Alberquilla

The development of advanced gene and cell therapies for the treatment of genetic diseases requires reliable animal and cellular models to test their efficacy. Moreover, the availability of the target human primary cells of these therapies is reduced in many diseases. The development of endonucleases that can cut into specific sites of the cell genome, as well as the repair of the generated break by non-homologous end-joining, results in a variety of outcomes, insertions, deletions, and inversions that can induce the disruption of any specific gene. Among the many methods that have been developed for gene editing, CRISPR-Cas9 technology has become one of the most widely used endonuclease tools due to its easy design and its low cost. It has also been reported that the use of two guides, instead of just the one required, reduces the outcomes of non-homologous end joining mainly to the precise genomic sequences between the cutting sites of the guides used. We have explored this strategy to generate useful cellular and animal models. Different distances between the two guides have been tested (from 8 to 500 bp apart), and using the optimal range of 30-60 bp we have obtained a human primary cellular model of a genetic disease, pyruvate kinase deficiency, where the availability of the target cells is limited. We have also generated an in vivo model of glycolate oxidase (GO) deficiency, which is an enzyme involved in the glyoxylate metabolism following the same strategy. We demonstrate that the use of two-guide CRISPR-Cas9-induced non-homologous end joining is a feasible and useful tool for disease modeling, and it is most relevant to those diseases in which it is difficult to get the cells that will be genetically manipulated.

Gene knockout

Non-homologous end joining

10.1016/j.omtm.2020.10.007

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Efficient and Fast Generation of Relevant Disease Mouse Models by In Vitro and In Vivo Gene Editing of Zygotes

The CRISPR Journal (2022)

Raquel Sánchez-Baltasar Aida García-Torralba Virginia Nieto-Romero Angustias Page Andrea Molinos-Vicente

Knockout mice for human disease-causing genes provide valuable models in which new therapeutic approaches can be tested. Electroporation of genome editing tools into zygotes,

SMARCA4

10.1089/crispr.2022.0013

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In vitroandIn vivoGenetic Disease Modelling via NHEJ-precise deletions using CRISPR/Cas9

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Sergio López-Manzaneda Isabel Ojeda-Pérez Nerea Zabaleta Aida García-Torralba Omaira Alberquilla

ABSTRACT Development of advanced gene and cell therapies for the treatment of genetic diseases requires confident animal and cellular models to test their efficacy and is crucial in the cases where no primary samples from patients are available. CRISPR/Cas9 technology, has become one of the most spread endonuclease tools for editing the genome at will. Moreover, it is known that the use of two guides tends to produce the precise deletion between the guides via NHEJ. Different distances between guides were tested (from 8 to 500 base pairs). We found that distances between the two cutting sites and orientation of Cas9 protein-DNA interaction are important for the efficiency within the optimal range (30-60 bp), we could obtain new genetically reproducible models for two rare disease, a Pyruvate Kinase Deficiency model, using human primary cells, and a (for in vivo primary hyperoxaluria therapeutic mouse model. We demonstrate that the use of a 2-guideRNAs at the optimal distance and orientation is a powerful strategy for disease modelling in those diseases where the availability of primary cells is limited.

Pyruvate kinase deficiency

10.1101/2020.03.25.007260

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Citations (0)