Advances in therapies for neurological lysosomal storage disorders

Research output: Contribution to journalReview articlepeer-review


Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two-thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood-brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood-brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug-related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS-targeted treatments for neurological LSDs with a particular emphasis on gene therapy-based modalities, such as Adeno-Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.
Original languageEnglish
Pages (from-to)874-905
Number of pages32
JournalJournal of Inherited Metabolic Disease
Issue number5
Early online date20 Apr 2023
Publication statusPublished - 7 Sept 2023


  • AAV
  • blood–brain barrier
  • gene therapy
  • lentiviral vectors
  • lysosomal storage disorders
  • mucopolysaccharidosis
  • stem cells


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