1:Division of Cell Technology, Biomedical Innovation Unit, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid 28040. Spain.; 2:Programa de Medicina Regenerativa, CIMA Universidad de Navarra. Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain; 3:San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy. “Vita-Salute San Raffaele” University, Milan, Italy; 4:Pathology Department, Hospital Universitario de Canarias, Universidad La Laguna. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Tenerife, Spain

Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disease with hepatic origin caused by mutations in the AGXT1 gene which codes for the liver enzyme alanine-glyoxylate aminotransferase. PH1 patients suffer from oxalate overproduction that can result in end-stage renal disease and life-threatening oxalosis. Thirty percent patients show infantile onset. The only curative treatment is liver and kidney double-transplant. Therefore, new therapeutic approaches are needed. In vivo lentiviral vector-based gene therapy has emerged as a promising therapy for liver monogenic diseases, especially in pediatric patients. A preclinical study of in vivo LV gene therapy in a PH1 mouse model has been conducted. Adult Agxt1 KO mice were intravenously injected with different doses of a hepatocyte-specific LV expressing an EGFP reporter gene or an AGXT cDNA. Mice treated with the reporter LV revealed a transduction percentage up to 10%. To analyse the reversion of the PH1 phenotype, three weeks after LV injection of equivalent doses of LV expressing the AGXT cDNA, mice were subjected to an ethylene glycol challenge to induce overload in oxalate production. Treated mice showed a significant reduction in urine oxalate overproduction, prevention of weight loss, and no signs of nephrocalcinosis, achieving a partial pathological phenotype reversion of the PH1 pathology. Due to the cell-autonomous character of this disease, the observed phenotype reversion with such a limited number of corrected cells (estimated in 10%) opens the possibility of using LV for the treatment of PH1 and lays the foundations for future therapeutic approaches for PH1.