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In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease
Published on: December 20, 2017
Targeted nanoliposomes to improve enzyme replacement therapy of Fabry disease
Judit Tomsen-Melero1,2, Marc Moltó-Abad1,3, Josep Merlo-Mas4
1Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain.
Abstract:
The central nervous system represents a major target tissue for therapeutic approach of numerous lysosomal storage disorders. Fabry disease arises from the lack or dysfunction of the lysosomal alpha-galactosidase A (GLA) enzyme, resulting in substrate accumulation and multisystemic clinical manifestations. Current enzyme replacement therapies (ERTs) face limited effectiveness due to poor enzyme biodistribution in target tissues and inability to reach the brain. We present an innovative drug delivery strategy centered on a peptide-targeted nanoliposomal formulation, designated as nanoGLA, engineered to selectively deliver a recombinant human GLA (rhGLA) to target tissues. In a Fabry mouse model, nanoGLA demonstrated improved efficacy, inducing a notable reduction in Gb3 deposits in contrast to non-nanoformulated GLA, even in the brain, highlighting the potential of the nanoGLA to address both systemic and cerebrovascular manifestations of Fabry disease. The EMA has granted the Orphan Drug Designation to this product, underscoring the potential clinical superiority of nanoGLA over authorized ERTs and encouraging to advance it toward clinical translation.
Insights
A novel nanoliposomal drug delivery system, nanoGLA, effectively targets Fabry disease by delivering alpha-galactosidase A enzyme to tissues, including the brain. This innovative approach shows promise for treating systemic and cerebrovascular manifestations.
Area of Science:
- Biochemistry
- Nanotechnology
- Pharmacology
Background:
- Lysosomal storage disorders, like Fabry disease, affect multiple organs due to enzyme deficiency.
- Current enzyme replacement therapies (ERTs) for Fabry disease have limited efficacy, particularly in reaching the central nervous system.
- Fabry disease is caused by deficient alpha-galactosidase A (GLA) activity, leading to substrate accumulation.
Purpose of the Study:
- To develop and evaluate a peptide-targeted nanoliposomal formulation (nanoGLA) for enhanced delivery of recombinant human GLA (rhGLA).
- To assess the efficacy of nanoGLA in reducing substrate accumulation in a preclinical model of Fabry disease.
- To investigate the potential of nanoGLA to address both systemic and brain-related manifestations of Fabry disease.
Main Methods:
- Development of a peptide-targeted nanoliposomal drug delivery system (nanoGLA) carrying rhGLA.
- Administration of nanoGLA to a mouse model of Fabry disease.
- Assessment of Gb3 deposit reduction in various tissues, including the brain, compared to non-nanoformulated GLA.
Main Results:
- nanoGLA demonstrated superior efficacy in reducing Gb3 deposits compared to non-nanoformulated GLA.
- Significant reduction of Gb3 deposits was observed in the brain, indicating successful cerebrovascular delivery.
- The European Medicines Agency (EMA) granted Orphan Drug Designation to nanoGLA.
Conclusions:
- nanoGLA represents an innovative therapeutic strategy for Fabry disease with improved biodistribution and efficacy.
- The nanoliposomal formulation shows potential for treating both systemic and neurological aspects of Fabry disease.
- nanoGLA's promising preclinical results and regulatory designation support its advancement towards clinical trials.
