Maria Grazia Roncarolo lab
Maria Grazia Roncarolo's lab leads efforts to translate scientific discoveries in genetic diseases and regenerative medicine into novel patient therapies, including treatments based on stem cells and gene therapy.Dr. Roncarolo, a pediatric immunologist by training, spent her early career in Lyon, France, where she focused on severe inherited metabolic and immune diseases, including severe combined immunodeficiency (SCID), better known as “bubble boy disease.” Dr. Roncarolo was a key member of the team that carried out the first stem cell transplants given before birth to treat these genetic diseases.
While studying inherited immune diseases, Dr. Roncarolo discovered a new class of T cells. These cells, called T regulatory type 1 cells, help maintain immune-system homeostasis by, among other things, preventing autoimmune diseases and helping the immune-system tolerate transplanted cells and organs. Recently, she completed the first clinical trial using T regulatory type 1 cells to prevent severe graft-versus-host disease in leukemia patients undergoing allogeneic hematopoietic stem cell transplantation.
Dr. Roncarolo worked for several years at DNAX Research Institute for Molecular and Cellular Biology in Palo Alto, where she contributed to the discovery of novel cytokines and she studied the role of cytokines in induction of tolerance and in promotion of stem cell growth and differentiation.
Dr. Roncarolo developed new gene-therapy approaches, which she pursued as director of the Telethon Institute for Cell and Gene Therapy at the San Raffaele Scientific Institute in Milan. She was the principal investigator leading the successful gene therapy trial for SCID patients lacking adenosine deaminase (ADA), a severe life-threatening disorder. The trial is now considered the gold standard for gene therapy in inherited immune diseases. Under her direction, the Institute has been seminal in showing the efficacy of gene therapy for other untreatable inherited metabolic diseases and primary immunodeficiencies.
Dr. Roncarolo’s goal at Stanford is to build the teams and infrastructures to fast track stem cell and gene therapy to the clinic and to bring basic-science discoveries to patients. In addition, her laboratory continues to work on T regulatory cell-based treatments to induce tolerance after transplantation of allogeneic tissue stem cells. She recently published in Nature Medicine new biomarkers for T regulatory type 1 cells, which will be used to purify the cells and to track them in patients. She is also investigating genetic chronic inflammatory and autoimmune diseases due to impairment in T regulatory cell functions.
- gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO molecular medicine 2017; 9 (6): 737-740 Hide More
Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial.
2016; 388 (10043): 476-487
Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT).This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure [GMFM] score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov, number NCT01560182.Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18-54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients [grade 3 in four of five patients]). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% [range 14·0-95·6] lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites.Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up.Italian Telethon Foundation and GlaxoSmithKline.
View details for DOI 10.1016/S0140-6736(16)30374-9
View details for PubMedID 27289174
Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency
2016; 128 (1): 45-54
Adenosine deaminase (ADA) deficiency is a rare, autosomal-recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant from an HLA-matched sibling donor, although <25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34(+)-enriched cell fraction that contained CD34(+) cells transduced with a retroviral vector encoding the human ADA complementary DNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median, 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n = 17, patient 1 data not available). Immune reconstitution was demonstrated by normalization of T-cell subsets (CD3(+), CD4(+), and CD8(+)), evidence of thymopoiesis, and sustained T-cell proliferative capacity. B-cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details were registered at www.clinicaltrials.gov as #NCT00598481.
View details for DOI 10.1182/blood-2016-01-688226
View details for Web of Science ID 000379249600012
View details for PubMedID 27129325
- Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3(+) T-regs SCIENCE TRANSLATIONAL MEDICINE 2015; 7 (289) Hide More
- Immunological outcome in haploicentical-HSC transplanted patients treated with IL-10-anergizec donor T Cells FRONTIERS IN IMMUNOLOGY 2014; 5 Hide More