Oral small molecule therapy for lysosomal storage diseases

Area of Science:

• Biochemistry
• Pharmacology
• Genetics

Background:

• Enzyme replacement therapy (ERT) has been the standard treatment for lysosomal storage disorders (LSDs) for over two decades.
• Current ERT approaches exhibit limitations, particularly for neuronopathic LSDs, due to poor tissue distribution, immunological intolerance, and incomplete restoration of cellular homeostasis.

Purpose of the Study:

• To review the current landscape of small molecule therapeutics for lysosomal storage disorders.
• To explore how small molecule drugs can overcome the limitations of traditional enzyme replacement therapy.

Main Methods:

• Review of existing literature on small molecule drug development for LSDs.
• Analysis of therapeutic strategies including substrate synthesis inhibition, pharmacological chaperones, and proteostasis modification.

Main Results:

• Several oral small molecule drugs are approved or in advanced clinical trials for LSDs.
• These drugs demonstrate potential for wide tissue distribution, including the central nervous system (CNS).
• Approaches like substrate reduction therapy and chaperone therapy show promise in addressing LSD pathophysiology.

Conclusions:

• Oral small molecule drugs represent a significant advancement in LSD treatment, offering potential to overcome ERT limitations.
• Further investigation and clinical development of these agents are crucial for improving patient outcomes in LSDs.