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GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of β-galactosidase (βgal) and subsequent accumulation of GM1 ganglioside in lysosomes. One of the pathological aspects of GM1 gangliosidosis, and other storage disorders, is impaired autophagy, i.e., a reduced fusion of autophagosomes and lysosomes to degrade cellular waste. Enzyme replacement therapy (ERT) can effectively treat systemic deficiency but is limited by immunogenicity and shortened half-life of intravenously administered enzyme. In this paper, we report a hyaluronic acid-b-polylactic acid (HA-PLA) polymersome delivery system that can achieve an enzyme-responsive and sustained delivery of βgal to promote the cell’s self-healing process of autophagy. HA-PLA polymersomes have an average diameter of 138.0 ± 17.6 nm and encapsulate βgal with an efficiency of 77.7 ± 3.4%. In the presence of model enzyme Hyaluronidase, HA-PLA polymersomes demonstrate a two-fold higher release of encapsulant than without enzyme. We also identified reduced autophagy in a cellular model of GM1 Gangliosidosis (GM1SV3) compared to healthy cells, illustrated using immunofluorescence. Enhanced autophagy was reported in GM1SV3 cells treated with βgal-loaded polymersomes. Most notably, the fusion of lysosomes and autophagosomes in GM1SV3 cells returned to normal levels of healthy cells after 24 h of polymersome treatment. The HA-PLA polymersomes described here can provide a promising delivery system to treat GM1 Gangliosidosis.
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Therapeutic developments for neurodegenerative GM1 gangliosidosis
GM1 gangliosidosis (GM1) is a rare but fatal neurodegenerative disease caused by dysfunction or lack of production of lysosomal enzyme, β-galactosidase, leading to accumulation of substrates. The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing. However, effectiveness is limited for neuropathic GM1 due to the restrictive nature of the blood–brain barrier (BBB). ERT and SRT alleviate substrate accumulation through exogenous supplementation over the patient’s lifetime, while gene editing could be curative, fixing the causative gene,GLB1, to enable endogenous enzyme activity. Stem cell therapy can be a combination of both, withex vivogene editing of cells to cause the production of enzymes. These approaches require special considerations for brain delivery, which has led to novel formulations. A few therapeutic interventions have progressed to early-phase clinical trials, presenting a bright outlook for improved clinical management for GM1.
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- Award ID(s):
- 2047697
- PAR ID:
- 10503726
- Publisher / Repository:
- Frontiers In
- Date Published:
- Journal Name:
- Frontiers in Neuroscience
- Volume:
- 18
- ISSN:
- 1662-453X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fnins.2024.1392683
