Gene therapy for diseases involving the central nervous system- TherCNS

• Dr. Miguel Chillón
• Dr. Assumpció Bosch
• Dr. Lydia Giménez-Llort

The research activity of our group is aimed at defining, characterizing and applying gene therapy strategies for neurodegenerative and neurodevelopmental diseases.

To achieve this, our 3 main strategic objectives are:

1. Gene therapy for rare diseases affecting the central nervous system (Spastic Paraplegia type 52 -SPG52-; GNB1 encephalopathy; Megalencephalic leukoencephalopathy with subcortical cysts (MLC), Wolfram Syndrome, Amyotrophic Lateral Sclerosis (ALS) and Rett's syndrome) using AAV vectors. In all these diseases, we are working on murine models of the disease as a proof of concept and for some of them we are combining the animal experimentation in conjunction with fibroblasts and neurons, or other nervous system cells derived from patients' iPSCs. Evaluation of the degree of correction is evaluated by proteomics and transcriptomics analysis to study the molecular mechanisms involved, in conjunction with immunohistochemical analysis and memory and behavior tests.
2. Study of the molecular mechanisms involved in cognitive deficits in aging and Alzheimer's. We are using murine models of Alzheimer's and in murine and primate models for non-pathological aging to test new therapeutic proteins using AAV vectors with the ability to cross the blood-brain barrier. We are evaluating the degree of correction by proteomics and transcriptomics analysis to study the molecular mechanisms involved in conjunction with immunohistochemical analysis and memory and behavior phenotyping.
3. Generation and production of viral vectors for gene therapy; Development of viral vectors. We are performing basic research in virology and creating of a new library of new variants of AAVs for specific target of CNS cells through the blood brain barrier, as well as experiments to increase the capacity of gene loading and scaling up of viral productions in suspension.

1. Terapia génica para esclerosis lateral amiotrófica dirigida a estimular la neuroprotección y la modulación de la neuroinflamación. PID2020-116735RB-I00. (Funded by: Ministerio Ciencia Innovación. Plan Nacional).
2. Molecular and functional characterization of new recombinant chimeric chronokines. Implications for cognitive decline associated with aging. PID2019-104034RB-I00. (Funded by: MICIU/AEI/10.13039/501100011033).
3. Chronokine gene therapy, a new approach to tackle amyotrophic lateral sclerosis. 2021 PROD 00030. (Funded by AGAUR).
4. Gene therapy to treat Megalencephalic Leukodystrophy with subcortical cysts (MLC). 2022-00412. (Funded by: ELA International).
5. Personalized gene therapy for MECP2 using CRISPR/Cas9 technology together with AAV administration in 3D cell cultures and Kl mice. EJP RD JTC 2020. AC20/00051. (Funded by: European Joint Programme-Rare Diseases and ISC-III)
6. Terapias avanzadas. RD21/0017/0008. (Funded by: ISCIII. REDES DE INVESTIGACIÓN COOPERATIVA ORIENTADAS A RESULTADOS EN SALUD, RICORS).

• PID2019-104034RB-I00 (funded by MICIU/AEI/10.13039/501100011033)
• PID2020-116735RB-I00 (funded by MICIU/AEI/10.13039/501100011033)

• Leal-Julià M., Vilches J., Onieva A., Verdés S., Sánchez A., Chillón M., Navarro X., Bosch A. Proteomic quantitative study of dorsal root ganglia and sciatic nerve in type 2 diabetic mice. Molecular Metabolism, (2022) 55:101408. doi.org/10.1016/j.molmet.2021.101408.
• Roig-Soriano J, Griñán-Ferré C, Espinosa-Parrilla JF, Abraham C, Bosch A, Pallàs M, Chillon M. AAV-mediated expression of secreted and transmembrane aKlotho isoforms rescue relevant aging hallmarks in senescent SAMP8 mice. Aging Cell (2022), 00:e13581. doi: 10.1111/acel.13581.
• Edo Á, Calvo-Barreiro L, Eixarch H, Bosch A, Chillón M, Espejo C. Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis. Neurotherapeutics (2022), 9(5):1617-1633. doi: 10.1007/s13311-022-01279-8.
• A Muntsant, F Jiménez-Altayó, L Puertas-Umbert, E Jiménez-Xarrie, E Vila, L Giménez-Llort. Sex-dependent end-of-life mental and vascular scenarios for compensatory mechanisms in mice with normal and ad-neurodegenerative aging. Biomedicines (2022) 9 (2), 111. DOI: 10.3390/biomedicines9020111.
• L Giménez-Llort, D Marin-Pardo, P Marazuela, M Hernández-Guillamón. Survival Bias and Crosstalk between Chronological and Behavioral Age: Age-and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging. Biomedicines (2021) 9 (6), 636. DOI: 10.3390/biomedicines9060636
• Mòdol-Caballero G, García-Lareu B, Herrando-Grabulosa M, Verdés S, López-Vales R, Pagès G, Chillon M, Navarro X, Bosch A. Specific expression of Glial-Derived Neurotrophic Factor in muscles as gene therapy strategy for Amyotrophic Lateral Sclerosis. Neurotherapeutics (2021); 18(2):1113–1126, doi.10.1007/s13311-021-01025-6.
• Sanchez, A, García-Lareu B, Puig M, Prat E, Ruberte J, Chillon M, Nunes V, Estevez R, Bosch A. Cerebellar Astrocyte Transduction as Gene Therapy for Megalencephalic Leukoencephalopathy. Neurotherapeutics (2020); 17(4):2041-2053. doi:10.1007/s13311-020-00865-y. PMID: 32372403
• Mòdol-Caballero G, Herrando-Grabulosa M, García-Lareu B, Solanes N, Verdés S, Osta R, Francos-Quijorna I, López-Vales R, Calvo AC, Bosch A*, Navarro X*. Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1G93A ALS mice. Neurobiology of Disease (2020); 37:104793. doi.org/10.1016/j.nbd.2020.104793. PMID: 32032731. *Corresponding autors.
• Pagès G., Giménez-Llort L., García-Lareu B., Ariza L., Navarro M., Casas C., Chillón M., Bosch A. Intrathecal AAVrh10 corrects biochemical and histological hallmarks of mucopolysaccharidosis VII mice and improves behavior and survival. Human Molecular Genetics (2019); 28, 3610–3624. doi:10.1093/hmg/ddz220. PMID: 31511867.
• Baeta-Corral R, Johansson B, Giménez-Llort L. Long-term treatment with low-dose caffeine worsens BPSD-like profile in 3xTg-AD mice model of Alzheimer’s disease and affects mice with normal aging. Frontiers in Pharmacology (2019) 9, 79. DOI: 10.3389/fphar.2019.01061
• A. Massó, A. Sánchez, A. Bosch, L. Gimenez-Llort, M. Chillon. Secreted-Klotho isoform protects against age-dependent memory deficits. Molecular Psychiatry. Sep;23(9):1-11. (2018).
• M. Miralles, H. Eixarch, M. Tejero, C. Costa, K. Hirota, AR. Castaño, M. Puig, G. Stockinger, X. Montalban, A. Bosch, C. Espejo, M. Chillon. Clinical and histopathological amieloration of experimental autoimmune encephalomyelitis by AAV vectors expressing soluble IL23 receptor. Neurotherapeutics. Oct;14(4):1095-1106 (2017).