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Lysosomal Storage Diseases
1Section of Biochemical Genetics, Division of Human and Molecular Genetics, Division of Neurology, Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA.
Abstract:
Lysosomal storage disorders (LSDs), over 40 different diseases, are now considered treatable disorders. Only a few short years ago, Lysosomal storage disorders were seen as interesting neurodegenerative disorders without any potential for treatment. Effective treatment strategies such as bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and glycolipid synthesis inhibition have been developed in the last 20 years and continue to be researched and evaluated. Bone marrow transplantation began approximately 15 years ago and has shown benefit for some of the lysosomal storage disorders. In order to be effective, the transplant must be performed early in the course of the disease, before the development of irreversible neurologic damage. Diseases such as Hurler appear to respond to BMT, however, improvement in bone disease is much less vigorous than responses in other organs. Krabbe disease responds if the transplant is performed before irreversible signs of neurologic damage appear. Metachromatic leukodystrophy may respond if the transplant can be performed early enough although peripheral nerve findings appear to progress. Other diseases, eg, GM1- and GM2-gangliosidoses do not appear to be altered by BMT. Despite its high cost, ERT has been very effective treatment for type I (non-neuronopathic) Gaucher disease. Enzyme replacement therapy for other LSDs, including ERT for Fabry and Pompe diseases, which are planned to be imminently introduced, and other enzymes such as for Morquio and Hunter diseases that are in the study phases, may be marketed in the very near future. Glycolipid inhibitors, such as N-butyldeoxynijirimycin (OGS-918), have been effective in reducing the liver and spleen volume in type I Gaucher disease. These oral inhibitors may prove to be important adjuncts to ERT and provide the advantage of being able to cross the blood/brain barrier, which limits enzyme access to brain. Currently, clinical studies are being conducted on patients with type III Gaucher disease and Fabry disease using OGS-918. Other, potentially more specific, glycolipid inhibitors are being developed.
Insights
Lysosomal storage disorders are now treatable thanks to advancements like bone marrow transplantation and enzyme replacement therapy. Ongoing research into glycolipid synthesis inhibitors offers new hope for managing these complex genetic conditions.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Lysosomal storage disorders (LSDs) were historically considered untreatable neurodegenerative conditions.
- Recent decades have seen significant progress in developing therapeutic strategies for LSDs.
Purpose of the Study:
- To review the current and emerging treatment modalities for lysosomal storage disorders.
- To evaluate the efficacy and limitations of existing and novel therapeutic approaches.
Main Methods:
- Review of bone marrow transplantation (BMT) efficacy in specific LSDs.
- Assessment of enzyme replacement therapy (ERT) for various LSDs, including Gaucher, Fabry, and Pompe diseases.
- Evaluation of glycolipid synthesis inhibitors, such as N-butyldeoxynijirimycin (OGS-918), for LSD management.
Main Results:
- BMT shows benefit for some LSDs (e.g., Hurler, Krabbe) if performed early, but effectiveness varies and may not address all symptoms.
- ERT is highly effective for type I Gaucher disease and is expanding to other LSDs like Fabry and Pompe diseases.
- Glycolipid inhibitors demonstrate efficacy in reducing organ volume (e.g., Gaucher disease) and show potential for crossing the blood-brain barrier.
Conclusions:
- LSDs are increasingly recognized as treatable conditions due to therapeutic innovations.
- BMT, ERT, and glycolipid synthesis inhibitors represent key treatment strategies with ongoing development and evaluation.
- Future research focuses on improving existing therapies and developing targeted inhibitors for better LSD management, including neurological manifestations.