Research and discovery in Hematopoietic Cell&Gene Therapy

Research Activity

The activity of the group is devoted to generating novel therapeutic paradigms and clinical translation of new platforms based on the use of genetically engineered hematopoietic cells in multiple disease areas.

Inherited neurometabolic diseases of childhood

Our group is historically focused on the development of novel treatment approaches based on the use of genetically engineered hematopoietic stem and progenitors cells (HSPCs) for the treatment of inborn errors of metabolism severely affecting the central nervous system (CNS). The therapeutic potential of HSPC gene therapy in these conditions is based on their ability to repopulate the myeloid compartment of the recipient, including microglia in the CNS, with a transplant-derived, mature progeny able to express therapeutic transcripts and exert neuro-immunomodulatory and neuroprotective functions. The transplant progeny in the CNS recapitulates most of microglia functional features and can: i) attenuates or even reverse the detrimental effects of microglia activation response on other CNS cell types, such as neurons, thus mitigating CNS pathology; ii) restores a physiological myeloid cell/microglia function, including efficient scavenging, within the CNS with the potential to clear accumulated debris and undegraded molecules, including storage material; iii) provides a new effective source of therapeutic molecules, such as lysosomal enzymes for LSDs, within the CNS through genetic engineering; the functional protein could also be secreted and provided to neighboring cells. The curative potential of this approach can be further enhanced by the use of optimized protocols for rapid reconstitution of myeloid cell populations in the brain and spinal cord by the transplanted cells/their progeny that are being explored and developed in the laboratory, based on innovative routes for the delivery of the engineered HSPCs or on genetic modification of the HSPCs to provide them with an in vivo repopulation advantage in the CNS. These novel approaches are exploited for developing novel treatment opportunities for neurometabolic disorders of childhood with unmet medical need.

Acquired neurodegenerative diseases

The knowledge and technology developed by our group towards the treatment of neurometabolic disorders of childhood is now exploited for pioneering research in the area of adult-onset neurodegenerative disorders that share with the former conditions many pathogenic mechanisms. Among others, we are working on Frontotemporal Dementia (FTD) with the working hypothesis that achieving brain replacement of the lysosomal protein progranulin (GRN) is a rational therapeutic approach for familial FTD forms associated to GRN mutations, and on Alzheimer’s disease associated to Trem2 mutations, to assess the therapeutic potential of a TREM2-directed microglia engineering. To ensure the successful application of HSC gene therapy to these conditions, we are also focused on more basic studies aimed at further unraveling the mechanisms of microglia maintenance in physiological and pathological conditions, as well as the modalities of myeloid cell/microglia replacement following HSPC transplantation. Goal is the development of translational protocols allowing selective and specific targeting and transplantation of populations with the potential of contributing to microglia turnover. Moreover, in this same setting regulated expression of therapeutic genes in mature microglia is being pursued by gene transfer and gene editing approaches. Industrial alliances partially support these research projects.

Autoimmune disorders

The use of autologous hematopoietic cell transplantation (HCT) has been widely explored in the context of randomized multicenter clinical trials as a treatment option for autoimmune diseases, such as multiple sclerosis (MS) and type 1 diabetes (T1D). The aim behind this approach resides within the immunoregulatory properties of HSPCsand it is based on the possibility to permanently reprogram an auto-aggressive immune system towards a de novo self-tolerant immune repertoire by HSPC transplantation. Indeed, the expansion and reinfusion of autologous HSPCs was demonstrated to be a potent therapy in reverting hyperglycemia in T1D patients, while several data demonstrate that adoptive transfer of HSPCs, either in pharmacologically conditioned or unconditioned MS subjects allows the homing of immune-modulatory cells in the affected areas of the CNS. In this context, the evidence on the role of the immune-regulatory factor programmed death-ligand 1 (PD-L1) in HSPC immunobiology has opened the possibility to establish novel therapeutic strategies based on PD-L1 expression in HSPCs to treat autoimmune diseases as MS and T1D.Considering both the common autoimmune mechanisms underlying T1D and MS, and the role of the PD-1/PD-L1 axis in both diseases, the improvement of immuno-regulatory properties of HSPCs by expression of PD-L1 may result in a therapeutic benefit in MS and T1D upon transplantation. Our data in T1D and MS animal models provide support for this concept. In the setting of Sponsored research programs with Altheia Science, a spin-off of the University of Padua, we are developing this concept in the setting of translational studies towards clinical testing.

Pediatric cancer collaborative projects have been established within our Division combining the local unique expertise in pediatric oncology, advanced diagnostics and target discovery with the hematopoietic cell gene transfer and gene therapy expertise of the Biffi’s group

These projects are devoted to exploring the possibility of identifying and targeting unique surface tumor antigens by cell-based immunotherapy. The most advanced project is focused on acute myeloid leukemia and exploits newly discovered AML-specific antigens for the development of a Chimeric Antigen Receptor (CAR) T cell approach. Available proof of concept data demonstrates not only the feasibility but also the efficacy of the proposed strategy, and the most promising targets and CARs are being exploited for translational purposes. Industrial alliances partially support these research projects.

β-hemoglobinopathies, namely β-Thalassemia and Sickle Cell Disease

HSPC gene therapy is an extremely promising approach for these conditions. Dr. Poletti in our laboratory is exploring an original, forward-looking gene therapy strategy for β-globin defects based on a non-viral approach, with a solid potential for clinical efficacy and translation, with a strategic design to maximize accessibility to the multitude of neglected children born with these lethal and devastating diseases in the poorest, and most affected, countries. See link to subarea.