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Pharmacological small molecules for the treatment of lysosomal storage disorders
B E Smid1, J M F G Aerts, R G Boot
1Academical Medical Center, Internal Medicine/Department of Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, Netherlands.
Importance Of The Field:
Inherited lysosomal storage diseases often cause severe disability and have a devastating effect on quality of life. Enzyme replacement therapy (ERT) forms a cornerstone in the treatment of lysosomal enzyme deficiencies. Although for some lysosomal disorders ERT is lifesaving, important intrinsic restrictions of the approach are limited access of infused enzyme to less accessible body compartments such as the CNS, the burden of frequent intravenous administration, the emergence of antibodies and the high associated costs. Pharmacological small molecules may overcome these limitations.
Areas Covered In This Review:
Several novel therapeutic approaches using small molecules are emerging: substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors and proteostasis regulators.
What The Reader Will Gain:
Based on an extensive literature search up until June 2010, we here review the various therapeutic approaches with small compounds, including those currently in clinical use and those that have entered clinical trials. Compounds that are still in the preclinical phase are also briefly discussed.
Take Home Message:
pharmacological small molecules are a new class of agents that show great promise for the treatment of lysosomal storage disorders.
Insights
Pharmacological small molecules offer a promising new treatment for inherited lysosomal storage diseases. These compounds may overcome limitations associated with enzyme replacement therapy (ERT), improving patient outcomes.
Area of Science:
- Biochemistry and Pharmacology
- Lysosomal Storage Diseases
- Drug Discovery and Development
Background:
- Inherited lysosomal storage diseases cause severe disability and reduced quality of life.
- Enzyme replacement therapy (ERT) is a primary treatment but has limitations.
- ERT limitations include poor central nervous system (CNS) penetration, frequent administration, antibody formation, and high costs.
Purpose of the Study:
- To review emerging therapeutic approaches using small molecules for lysosomal storage disorders.
- To discuss the potential of pharmacological small molecules to overcome ERT limitations.
Main Methods:
- Comprehensive literature search up to June 2010.
- Review of various therapeutic strategies involving small compounds.
- Inclusion of compounds in clinical use, clinical trials, and preclinical phases.
Main Results:
- Several novel small molecule therapeutic approaches are emerging.
- These include substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors, and proteostasis regulators.
- The review covers compounds in various stages of development, from preclinical to clinical use.
Conclusions:
- Pharmacological small molecules represent a new class of therapeutic agents.
- These agents show significant promise for treating lysosomal storage disorders.
- Small molecules may offer a more effective and accessible treatment alternative to ERT.
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