Therapeutic Approaches for Lysosomal Storage Disorders

Lysosomal storage disorders encompass a diverse group of inherited conditions characterised by deficient activity of specific lysosomal hydrolases, leading to progressive substrate accumulation and multi-system pathology. In recent years therapeutic strategies have broadened beyond conventional enzyme replacement therapy to include haematopoietic stem cell transplantation, gene therapy, substrate reduction and pharmacological chaperone approaches. Haematopoietic stem cell transplantation remains the only established intervention for a subset of disorders when performed early, utilising donor-derived microglial engraftment to deliver enzyme to the central nervous system. Enzyme replacement therapy has achieved substantial systemic benefit, but faces challenges in addressing neurological manifestations due to the blood–brain barrier. Gene therapy platforms, employing viral vectors delivered systemically or directly into the cerebrospinal fluid, aim to achieve long-term expression of functional enzyme in target tissues. Substrate reduction therapy seeks to restrain the biosynthesis of storage substrates and reduce lysosomal burden, while pharmacological chaperones stabilise misfolded enzymes to enhance residual activity. Parallel efforts to modulate lysosomal pH and stimulate autophagic clearance provide complementary means to restore intracellular homeostasis. Taken together, these approaches underscore a trend towards combination regimens, tailored to disease genotype and stage, with the goal of preserving organ function, ameliorating neurological decline and improving long-term outcomes worldwide.

Research from Nature Portfolio

High-resolution ultrastructural analysis in a murine model of a prototypical lysosomal storage disorder has delineated the earliest pathological changes in motor neuron terminals and peripheral nerves at asymptomatic and juvenile stages. This work revealed a “dying-back” pattern of degeneration that precedes overt demyelination, thereby informing the timing and targets of emerging neuroprotective therapies and guiding optimisation of gene delivery to vulnerable neuronal compartments.

Therapeutic Approaches for Lysosomal Storage Disorders publication trend

The graph below shows the total number of articles in therapeutic approaches for lysosomal storage disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Enzyme replacement therapy (ERT): Administration of recombinant lysosomal enzymes to clear stored substrates.

Haematopoietic stem cell transplantation (HSCT): Transplant of donor stem cells that differentiate into enzyme-secreting microglia.

Gene therapy: Use of viral vectors to deliver functional copies of defective lysosomal enzyme genes.

Substrate reduction therapy (SRT): Pharmacological inhibition of biosynthetic pathways to limit accumulation of storage substrates.

Pharmacological chaperone: Small molecule that binds and stabilises a misfolded enzyme, enhancing its folding and activity.

References

1. Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease. Scientific Reports (2016).
2. Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy. Cells (2023).
3. CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy. Journal of Experimental Medicine (2023).