Alessandra Biffi is actively involved in gene therapy trials for genetic diseases of childhood. Her research focuses on enhancing the efficacy of HSC-based therapeutic approaches for LSDs with severe nervous system involvement.

Hematopoietic stem cell (HSC) progeny can represent a vehicle for therapeutic molecule delivery to the Central Nervous System (CNS) upon transplantation in myeloablated host. This effect was demonstrated in animal models and patients affected by lysosomal storage disorders (LSDs)(Biffi, JCI 2004 and 2006; Visigalli, Blood 2010; Gentner, Sci Transl Med 2010; Biffi, Science 2013; Sessa, Lancet 2016). It is dependent on the reconstitution of CNS myeloid cells, eventually including microglia, by the transplanted HSCs and their progeny (Capotondo, PNAS 2012).

The Biffi lab showed that the therapeutic potential of HSC transplantation for treating NeuroDegenerative Diseases (NDDs) can be enhanced by means of:

1. gene transfer into the transplanted HSCs for increasing the production of therapeutic molecules delivered to the brain by transplanted HSC progeny (Biffi, Science 2013; Sessa, Lancet 2016);
2. the use of a pre-transplant conditioning aimed not only at HSC ablation from the bone marrow, but also at eliminating CNS microglia progenitors (Capotondo, PNAS 2012); and
3. delivery of HSCs within brain lateral ventricles, to further enhance CNS myeloid cell and microglia reconstitution by the transplanted HSCs.

The Biffi lab is pursuing these strategies in the context of innovative cell and gene therapy applications for neurodegenerative LSDs employing autologous HSCs transduced with lentiviral vectors (LVs) ubiquitously expressing the therapeutic gene of interest or allogeneic HSCs in the context of myeloablated patients.

The group is also applying these strategies to the more frequent NDDs of adulthood, such as Amyotrophic Lateral Sclerosis (ALS) or Alzheimer’s disease. Indeed, a key role has recently being attributed to microglia activation and neuro-inflammation as molecular mechanisms leading to tissue damage in NDDs and most innovative therapeutic strategies are aimed at targeting these events for therapeutic purposes.

Biosketch

Alessandra Biffi is the director of the Gene therapy Program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Her previous position was in Milano, at the San Raffaele Telethon Institute for Gene Therapy, where she trained and developed a Research and Clinical Unit dedicated to the treatment of lysosomal storage disorders (LSDs) by means of hematopoietic stem cell (HSC)-based approaches.

Biffi is actively involved in gene therapy trials for genetic diseases of childhood. Her specific research is dedicated at enhancing the efficacy of HSC-based therapeutic approaches for LSDs with severe nervous system involvement by:

1. fostering brain microglia replacement by donor cells after HSC transplantation upon detailed understanding of this phenomenon (Capotondo et al., PNAS 2012), and
2. enhancing the potential of enzyme delivery to the affected nervous system by means of the gene corrected progeny of the transplanted, lentiviral vector (LV)-transduced HSCs (Biffi et al., Science 2013; Sessa et al., Lancet 2016).