A5014815569- Virus-based gene therapy research
- CAR-T cell therapy research
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- CRISPR and Genetic Engineering
- Pancreatic function and diabetes
- Diabetes Management and Research
- Pediatric Hepatobiliary Diseases and Treatments
- Extracellular vesicles in disease
- Liver physiology and pathology
- Mesenchymal stem cell research
- Renal Diseases and Glomerulopathies
- Acute Lymphoblastic Leukemia research
- Neuroinflammation and Neurodegeneration Mechanisms
- Cannabis and Cannabinoid Research
- Neonatal and fetal brain pathology
- Chronic Kidney Disease and Diabetes
- Organ Transplantation Techniques and Outcomes
- Trypanosoma species research and implications
- Autoimmune and Inflammatory Disorders Research
- Genetic and Kidney Cyst Diseases
- RNA regulation and disease
- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Hemophilia Treatment and Research
Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele
2022-2025
The San Raffaele Telethon Institute for Gene Therapy
2012-2025
Istituti di Ricovero e Cura a Carattere Scientifico
2022-2025
Vita-Salute San Raffaele University
2015-2023
San Raffaele University of Rome
2013
Mario Negri Institute for Pharmacological Research
2005-2006
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment die within a few years of symptom onset. We used lentiviral vector to transfer functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, neurophysiological evidence late infantile MLD. After reinfusion the gene-corrected HSCs, extensive...
Preclinical studies establish the conditions for safe and effective correction of SCID-X1 by targeted gene editing hematopoietic stem cells.
The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors colonize the brain before birth has relevant implications for treatment various neurological diseases, including lysosomal storage disorders (LSDs), which hematopoietic cell transplantation (HCT) is applied to repopulate recipient myeloid compartment, microglia, with cells expressing defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points...
Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults hemophilia. However, the mostly episomal nature of AAV challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate host cell genome, that achieve efficient liver transfer mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation VIII...
Abstract Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail respond these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays major role. Here we show that monocyte-mediated gene delivery IFNα inhibits leukemia in mouse model. IFN therapy counteracts leukemia-induced expansion myeloid cells and imposes immunostimulatory program TME, shown by bulk single-cell transcriptome...
Metachromatic Leukodystrophy (MLD) is a rare inherited lysosomal storage disorder caused by the deficiency of Arylsulfatase A (ARSA). The disease manifests itself with broad spectrum clinical variants, all characterized progressive neurodegeneration in central and peripheral nervous systems. correlation between mutations ARSA gene, residual enzymatic activity associated mutated alleles patients' phenotype, which has been extensively drawn for common mutations, recently expanded to ones. In...
A defect in invariant NKT (iNKT) cell selection was hypothesized lysosomal storage disorders (LSD). Accumulation of glycosphingolipids (GSL) LSD could influence lipid loading and/or presentation causing entrapment endogenous ligand(s) within bodies or competition the selecting by stored lipids for CD1d binding. However, when we analyzed iNKT compartment newly tested animal models that accumulate GSL, glycoaminoglycans both, observed a defective only animals affected multiple sulfatase...
MicroRNAs are essential regulators of normal and malignant hematopoiesis. miRNAs relevant for gene therapy, since they can be exploited to fine-tune the expression profile vector constructs or alter viral tropism (Gentner&Naldini, 2012). We hematopoietic stem cell (HSC) specific miR-126 de-target transgene from primitive compartment (Gentner et al, 2010; Chiriaco 2014; Escobar 2014) described function in HSC where it regulates balance between quiescence self-renewal (Lechman here report a...
Lentiviral (LV)-based hematopoietic stem and progenitor cell (HSPC) gene therapy is becoming a promising alternative to allogeneic transplantation for curing genetic diseases. To potentially improve the efficacy, safety economic sustainability of HSPC transduction, we reasoned genetically manipulate only more potent CD34+CD38- HSPC, thereby improving maintenance in culture absence differentiating cells downscaling product by factor ten without compromising long-term engraftment. This...
Liver regeneration is supported by hepatocytes and, in certain conditions, biliary epithelial cells (BEC). BEC are bipotent stem cells, able to form organoids culture and engraft damaged livers. However, heterogeneity the homeostatic liver remains be fully elucidated. Here, we exploited vivo systemic lentiviral vector (LV) administration achieve efficient life-long gene transfer mice. We found that LV-marked retain organoid-formation potential respond damage, however, were less clonogenic...
Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: We have been developing a treatment for Hyper IgM 1, combined immunodeficiency caused by mutations in the X-linked CD40LG gene, homology driven recombination (HDR) gene editing using Cas9 viral donor template. Anticipating clinical translation, we designed suitable manufacturing process. Furthermore, as there is no consensus on characterization of products, developed assays to assess genomic outcomes...
Abstract Liver gene therapy with adeno-associated viral (AAV) vectors delivering a clotting factor transgene into hepatocytes has shown multi-year therapeutic benefit in adults hemophilia. However, anti-AAV pre-existing immunity and the mostly episomal nature of AAV vectors, currently challenges application AAV-vector mediated liver to people neutralizing antibodies young pediatric patients. We have developed lentiviral (LV), which integrate host cell genome, achieve stable efficient...