Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

Abstract

Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset. In the attempt to overcome these issues, gene therapy has been proposed as a valuable therapeutic option, either ex vivo, with target cells genetically modified in vitro, or in vivo, by inserting the genetic material with systemic or intra-parenchymal, in situ administration. In particular, the use of autologous haematopoietic stem cells (HSC) transduced with a viral vector containing a healthy copy of the mutated gene would allow supra-normal production of the defective enzyme and cross correction of target cells in multiple tissues, including the central nervous system. This review will provide an overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I).

Failure to clear developmental apoptosis contributes to the pathology of RNASET2-deficient leukoencephalopathy

“…We provide evidence to focus on therapies that can target the microglial population, such as gene therapy and haematopoietic stem cell transplantation. These therapies are already being used in clinical trials for LSDs and other types of leukodystrophies (Penati et al, 2017;Ohashi, 2019;Schiller et al, 2019) and could therefore be adapted to treat children suffering from RNAseT2-deficient leukoencephalopathy.…”

A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management

“…Gene therapy can be in vivo or ex vivo. In vivo gene therapy directly delivers gene products into the body via systematic or in situ administration (63). Ex vivo gene therapy involves modifying a patient's stem cells externally and then infusing them back into the body.…”

Transplantation as disease modifying therapy in adults with inherited metabolic disorders

“…Ex vivo gene therapy is in clinical trials for a number of IMDs. Autologous HSCT is part of this procedure as patients receive immunosuppression (Chandler and Venditti 2016;Bernardo and Aiuti 2016), to enable expansion of the transduced host cells, after which the host cells transduced with the desired genetic material are reinfused (Penati et al 2017). Although short-term outcomes of ex vivo gene therapy of clinical trials in various IMDs, such as metachromatic leukodystrophy (Sessa et al 2016) and X-ALD (Cartier et al 2009), have been reported, there were no adults included in these studies to allow comparison of the adult and pediatric outcomes.…”