Hematopoietic stem cell gene therapy for lysosomal storage disorders

SR-Tiget Unit
Alessandra Biffi, Head of Unit


Lysosomal storage disorders (LSDs) comprise a class of inherited diseases characterized by disruption of normal lysosomal function and accumulation of undegraded substrates. Despite sharing a similar pathogenic mechanism, the over 40 different described LSDs differ for disease-specific features. The main differences are represented by the pattern of visceral organ involvement and by the presence and severity of nervous system (NS) involvement. Hematopoietic stem cells transplantation (HCT) is an effective treatment for some LSDs. Its efficacy relies on the migration of donor cells of the monocyte lineage into disease target organs, where they replace the resident enzyme-deficient population, thus becoming a local and steady source of the functional enzyme. In the case of LSDs with NS involvement, HCT efficacy has been limited and the patients eligible for such procedure are a minority. The main reason for HCT failure in LSD patients with overt neurological symptoms or in those with early onset or aggressive infantile forms is the likely slow pace of replacement of resident tissue macrophages/histiocytes and microglia populations by the transplanted hematopoietic cell progeny as compared with the rapid progression of the primary disease. Due to this lag period, which is expected to be in the range of 12–24 months before initial disease stabilization, the more severe the phenotype and the longer the interval from onset of first symptoms to allogeneic HCT, the poorer the outcome. Hematopoietic stem cell (HSC)-mediated gene therapy has long been considered an attractive option for the treatment of LSDs, and in particular for NS manifestations. Firstly, it may substantially reduce allogeneic HCT side effects since the autologous procedure is expected to be associated to a reduced transplant-related morbidity and mortality, and avoids the risks of GvHD. Besides safety, the main and critical advantage of the use of genetically corrected autologous HSC as respect to their allogeneic counterpart resides in the possible improvement of the therapeutic potential of HCT in refractory LSDs by means of gene transfer. Indeed, autologous HSCs can be genetically modified to constitutively express higher than normal levels of the therapeutic enzyme and become a quantitatively more effective source of enzyme than normal donors’ cells, possibly also at the level of the affected CNS. Our preclinical and clinical research activity on Type I Mucopolysaccharidosis (MPS I), Glodoid Leukodystrophy (GLD, also known as Krabbe disease) and in Metachromatic Leukodystrophy (MLD), respectively, is devoted to the proof of feasibility and therapeutic relevance of this approach using as gene transfer vehicles advanced generation lentiviral vectors (LVs). Moreover, we are exploring the therapeutic mechanisms underlying disease correction in order to establish novel dynamic principles of therapy uniquely afforded by gene therapy, such as the advantages of enzyme overexpression and the modalities of its biodistribution, while at the same time providing new insights into biological processes of tissue homeostasis, such as microglia turnover at baseline and upon myeloablative conditioning.

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