Lysosomal Disorder Treatment Strategies

Lysosomal storage diseases comprise a diverse group of inherited disorders in which deficient lysosomal hydrolases lead to the accumulation of undegraded substrates and subsequent cellular dysfunction. Current treatment paradigms aim to restore enzyme activity, limit substrate accumulation and address downstream pathologies. Enzyme replacement therapy (ERT) delivers recombinant enzymes systemically but often fails to cross the blood–brain barrier. Haematopoietic stem cell transplantation (HSCT) provides a sustained source of enzyme from donor-derived cells and is most effective when performed early. Substrate reduction therapy (SRT) decreases the biosynthesis of storage molecules and may achieve central nervous system penetration. Emerging gene therapy approaches employ viral vectors for targeted, long-term expression of functional enzymes, while small-molecule chaperones and immunomodulatory agents seek to stabilise misfolded proteins, enhance intracellular trafficking and mitigate neuroinflammation. Integrated newborn screening and early intervention are critical to prevent irreversible tissue damage and to guide personalised, multimodal treatment strategies globally.

Research from Nature Portfolio

Recent clinical research has explored the use of a recombinant interleukin-1 receptor antagonist to treat neuroinflammation in Sanfilippo syndrome. A phase 1/2 trial demonstrated that administration of an interleukin-1 blocker was safe and well tolerated, with improvements in neurobehavioural and functional measures in the majority of participants. Dose escalation at mid-point evaluation was required in some cases to achieve optimal response, and mild injection site reactions were the most common adverse events. These findings support further investigation of targeted immunomodulation as a complement to enzymatic and gene-based therapies in mucopolysaccharidoses.

Lysosomal Disorder Treatment Strategies publication trend

The graph below shows the total number of articles in lysosomal disorder treatment strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Lysosomal storage disorder: A genetic condition in which defective lysosomal enzymes cause accumulation of unmetabolised substrates.

Enzyme replacement therapy: Intravenous infusion of recombinant enzymes to restore deficient lysosomal function.

Haematopoietic stem cell transplantation: Transplantation of donor stem cells capable of producing functional enzymes in recipient tissues.

Substrate reduction therapy: Pharmacological inhibition of substrate synthesis to limit storage accumulation.

References

1. Anakinra in Sanfilippo syndrome: a phase 1/2 trial. Nature Medicine (2024).
2. Low-molecular weight sulfated marine polysaccharides: Promising molecules to prevent neurodegeneration in mucopolysaccharidosis IIIA?. Carbohydrate Polymers (2023).
3. Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. Molecular Genetics and Metabolism (2016).
4. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet Journal of Rare Diseases (2011).
5. Enzyme replacement therapy: efficacy and limitations. Italian Journal of Pediatrics (2018).
6. The rapidly evolving view of lysosomal storage diseases. EMBO Molecular Medicine (2021).
7. Common and Uncommon Pathogenic Cascades in Lysosomal Storage Diseases*. Journal of Biological Chemistry (2010).