San Raffaele Telethon Institute for Gene Therapy

Goal 1. Advance HSC gene therapy to standard-of-care for rare genetic diseases

Hematopoietic stem cell gene therapy (HSC GT) may become standard-of-care and eventually first-line treatment for an increasing number of diseases by surpassing allogeneic HSC transplantation because of lower treatment-related short- and long-term morbidity and, in some cases, improved efficacy.

SR-Tiget Goal 1

ADA-SCID: Adenosine Deaminase Severe Combined Immunodeficiency; a- MAN: Alfa Mannosidases; ARO: Autosomal Recessive Osteopetrosis; B-THAL: BetaThalassemia DADA2: Adenosine Deaminase 2 Deficiency; GLD: Globoid Cell Leukodystrophy; HSC: Hematopoietic Stem Cells; MLD: Metachromatic Leukodystrophy; MPSIH/IVA/IVB: Mucopolysaccharidosis type 1 Hurler, type IVA and type IVB; SD: Sandhoff Disease; WAS: Wiskott-Aldrich Syndrome

SR-Tiget continues to be at the forefront of clinical development in this area, with >120 patients treated with HSC GT medicinal products for 5 different genetic diseases and 15 glioblastoma patients treated for a first-in-human and first-of-its-kind HSC GT mediated immunotherapy in a trial sponsored by Genenta in the OSR Adult Oncohematology Unit. Two of these therapies have now reached market registration in EU in collaboration with industry (Strimvelis for ADA-SCID in 2016 with GlaxoSmithKline and Libmeldy for MLD in 2020 with Orchard Therapeutics) and three more are in advanced development.

Despite these positive results from our Institute as well as other Centers worldwide have established the therapeutic value of autologous HSC GT, important hurdles remain to be overcome before expanding its application to a broader panel of diseases and making access to such treatments possible in broader clinical settings, including in countries with less developed health systems. These hurdles include the short and long-term toxicity of conditioning, the requirement for prolonged and specialized hospital care during hematopoietic recovery, the cost of vector production and ex vivo manipulation of a highly personalized cell product, the residual genotoxic risk of randomly integrating vectors and the unknown long-term resilience and clonal evolution of an exhaustively engineered hematopoietic graft. Moreover, several pathophysiological features, such as disease background, inflammation and aging affect the safety and efficacy of HSC GT.

We aim to address these hurdles in a comprehensive research program whose major objectives include:

  1. investigating biological processes and features of human HSC relevant for translation;
  2. improving HSC manipulation (harvest, transduction and processing);
  3. developing and test emerging non-genotoxic conditioning regimens;
  4. establishing novel readouts and further improve gene transfer safety;
  5. feeding a robust and innovative clinical trial pipeline, also addressing ways to ease the regulatory burden of clinical testing of novel ATMP to save costs and time, and facilitate access to a more sustainable treatment.

Many of the objectives related to HSC biology investigation and manipulation are also relevant for the development of gene editing strategies targeting HSCs (see GOAL 2).