Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis
GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis pre...
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MDPI AG
2022-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/16/2579 |
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| author | Jason Andrew Weesner Ida Annunziata Tianhong Yang Walter Acosta Elida Gomero Huimin Hu Diantha van de Vlekkert Jorge Ayala Xiaohui Qiu Leigh Ellen Fremuth David N. Radin Carole L. Cramer Alessandra d’Azzo |
| author_facet | Jason Andrew Weesner Ida Annunziata Tianhong Yang Walter Acosta Elida Gomero Huimin Hu Diantha van de Vlekkert Jorge Ayala Xiaohui Qiu Leigh Ellen Fremuth David N. Radin Carole L. Cramer Alessandra d’Azzo |
| author_sort | Jason Andrew Weesner |
| collection | DOAJ |
| description | GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine β-Gal fused to the plant lectin subunit B of ricin (mβ-Gal:RTB). We show that long-term, bi-weekly systemic injection of mβ-Gal:RTB in the <i>β-Gal</i><sup>−/−</sup> mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, β-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the β-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis. |
| first_indexed | 2024-03-09T09:58:57Z |
| format | Article |
| id | doaj.art-05df366dd2894f4e94a3be11fe6fa3d9 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T09:58:57Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-05df366dd2894f4e94a3be11fe6fa3d92023-12-01T23:33:38ZengMDPI AGCells2073-44092022-08-011116257910.3390/cells11162579Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-GangliosidosisJason Andrew Weesner0Ida Annunziata1Tianhong Yang2Walter Acosta3Elida Gomero4Huimin Hu5Diantha van de Vlekkert6Jorge Ayala7Xiaohui Qiu8Leigh Ellen Fremuth9David N. Radin10Carole L. Cramer11Alessandra d’Azzo12Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USABioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USABioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USABioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USABioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USABioStrategies, LC, P.O. Box 2428, State University, Jonesboro, AR 72467, USADepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAGM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine β-Gal fused to the plant lectin subunit B of ricin (mβ-Gal:RTB). We show that long-term, bi-weekly systemic injection of mβ-Gal:RTB in the <i>β-Gal</i><sup>−/−</sup> mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, β-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the β-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis.https://www.mdpi.com/2073-4409/11/16/2579lysosomal storage diseaseGM1ERTmβ-Gal:RTBCNS |
| spellingShingle | Jason Andrew Weesner Ida Annunziata Tianhong Yang Walter Acosta Elida Gomero Huimin Hu Diantha van de Vlekkert Jorge Ayala Xiaohui Qiu Leigh Ellen Fremuth David N. Radin Carole L. Cramer Alessandra d’Azzo Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis Cells lysosomal storage disease GM1 ERT mβ-Gal:RTB CNS |
| title | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis |
| title_full | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis |
| title_fullStr | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis |
| title_full_unstemmed | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis |
| title_short | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis |
| title_sort | preclinical enzyme replacement therapy with a recombinant β galactosidase lectin fusion for cns delivery and treatment of gm1 gangliosidosis |
| topic | lysosomal storage disease GM1 ERT mβ-Gal:RTB CNS |
| url | https://www.mdpi.com/2073-4409/11/16/2579 |
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