Targeting neurological abnormalities in lysosomal storage diseases

Area of Science:

• Neurology
• Genetics
• Biochemistry

Background:

• Lysosomal storage disorders (LSDs) are a group of genetic diseases characterized by the accumulation of undigested materials within lysosomes.
• Central nervous system (CNS) involvement is a common and severe feature of many LSDs, leading to significant neurological and psychiatric morbidity.
• Defective lysosomal function in the CNS disrupts normal cellular processes like autophagy, resulting in neurodegeneration and diverse clinical symptoms.

Purpose of the Study:

• To review the neurological and biobehavioral phenotypes associated with major classes of LSDs.
• To discuss current and emerging therapeutic strategies targeting neuropathology in LSDs.
• To propose focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening as a method to enhance therapeutic delivery to the CNS.

Main Methods:

• Literature review of neurological and psychiatric manifestations in LSDs.
• Analysis of therapeutic strategies under development for LSDs, focusing on CNS-targeted treatments.
• Discussion of focused ultrasound technology for BBB opening and its potential application in LSDs.

Main Results:

• LSDs share common downstream consequences in the CNS, including neurocircuitry dysfunction, neurodegeneration, and sensory, motor, cognitive, and psychological symptoms, despite unique genetic origins.
• Various therapeutic strategies are being developed to address the multifaceted pathology of LSDs.
• Enhanced delivery of disease-modifying therapies to the CNS remains a significant challenge.

Conclusions:

• Neuropathology is a critical component of LSDs, necessitating targeted therapeutic interventions.
• Focused ultrasound (FUS) offers a promising approach to overcome the BBB, potentially improving the efficacy of CNS-directed therapies for LSDs.
• Further research into FUS applications could revolutionize treatment strategies for LSDs affecting the central nervous system.