Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases
Inventors
DARIOS, Frédéric • Stevanin, Giovanni • Mochel, Fanny • BRANCHU, Julien • BOUTRY, Maxime
Assignees
Centre National de la Recherche Scientifique CNRS • Assistance Publique Hopitaux de Paris APHP • Institut National de la Sante et de la Recherche Medicale INSERM • Sorbonne Universite • Ecole Pratique des Hautes Etudes SAS • Institut du Cerveau et de La Moelle Epiniere ICM
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Publication Number
US-11065238-B2
Publication Date
2021-07-20
Expiration Date
Abstract
The present invention relates to inhibitors of gangliosides metabolism for treating motor neuron diseases, in particular hereditary spastic paraplegias.
Core Innovation
The invention provides compositions and methods for reducing ganglioside metabolism in a subject suffering from a motor neuron disease associated with hereditary spastic paraplegia (HSP), including SPG11, SPG4, and SPG7. The method uses inhibition of glucosylceramide synthase (GCS), and the disclosed approach also includes downregulating GM3 synthase to reduce ganglioside metabolism and related accumulation or aggregation processes for ganglioside species.
In hereditary spastic paraplegia, loss of SPG11 causes lysosomal dysfunction and ganglioside accumulation, including GM2 and GM3, or simple gangliosides such as GM2/GM3 and GD2/GD3, preceding neuronal death. GM2 is localized to Lamp1+ lysosomes and is associated with formation and accumulation of autolysosomes (Lamp1+/p62+), while ganglioside-lowering interventions modulate autolysosome formation and alter GM2 levels.
The patent text enumerates GCS inhibitors selected from imino sugars, ceramide analogs, carboxamides, carbamates, glycoside hydrolase chaperones, imiglucerase, and nucleic-acid gene-expression inhibitors. The nucleic-acid gene-expression inhibitor options include RNAi components, antisense or interfering RNAs, siRNA, shRNA, miRNA, ribozymes, DNAzymes, peptide nucleic acids, and locked nucleic acids, and the document also describes oral, topical, transdermal, intramuscular, subcutaneous, intravenous, parenteral, intranasal, and perispinal administration.
Claims Coverage
The provided claims center on one independent method claim directed to reducing ganglioside metabolism in an HSP subject by administering a glucosylceramide synthase (GCS) inhibitor. The claim set further refines this core concept with inhibitor classes, nucleic-acid gene-expression inhibitor modalities, administration routes, peripheral neuropathy, and imiglucerase.
Reducing ganglioside metabolism in HSP using a GCS inhibitor
A method for reducing ganglioside metabolism in a subject suffering from a motor neuron disease, comprising administering an inhibitor of glucosylceramide synthase (GCS), wherein the motor neuron disease is hereditary spastic paraplegia (HSP) selected from SPG11, SPG4, and SPG7.
GCS inhibitor selected from defined classes
The inhibitor of GCS is selected from an imino sugar, a ceramide analog, a carboxamide, a carbamate, a glycoside hydrolase chaperone, imiglucerase, and a nucleic acid inhibitor of gene expression.
Nucleic-acid gene-expression inhibitor modalities
The inhibitor is a nucleic acid inhibitor of gene expression selected from ribozymes, RNAi components, antisense or interfering RNAs, and chemically modified nucleic-acid inhibitor types including DNAzymes, peptide nucleic acids (PNA), and locked nucleic acids (LNA), including siRNA, shRNA, and miRNA.
Administration route selection
The inhibitor is administered using oral, topical, transdermal, intramuscular, subcutaneous, intravenous, parenteral, intranasal, or perispinal administration.
Peripheral neuropathy in the HSP subject
The HSP subject has peripheral neuropathy.
Imiglucerase as the GCS inhibitor
The GCS inhibitor is imiglucerase.
The claims coverage is centered on administering a GCS inhibitor to reduce ganglioside metabolism in an HSP subject (SPG11, SPG4, or SPG7). The refinements specify inhibitor classes, nucleic-acid modalities, administration routes, peripheral neuropathy, and imiglucerase.
Stated Advantages
Reduces ganglioside metabolism in a subject suffering from hereditary spastic paraplegia selected from SPG11, SPG4, and SPG7.
Ganglioside accumulation is described as preceding neuronal death.
Ganglioside-lowering interventions modulate autolysosome formation and alter GM2 levels.
Altering GM2 levels changes glutamate-triggered neuronal death.
Described rescue of zebrafish zspg11 model motor phenotype by miglustat.
Increased neuronal GM2 vesicular accumulation is reported across SPG11, SPG4, and SPG7 patient brain cortex, supporting gangliosides as a therapeutic target across HSP subtypes.
Reducing ganglioside metabolism is framed as neuroprotection.
Documented Applications
The disclosed approach is applied to subjects with hereditary spastic paraplegia (HSP) selected from SPG11, SPG4, and SPG7, and to models associated with SPG11 including a zebrafish zspg11 model.
Treating motor neuron diseases associated with hereditary spastic paraplegia (HSP), including SPG11, SPG4, and SPG7.
Reducing ganglioside metabolism in a subject suffering from a motor neuron disease.
Functional outcomes are reported in the context of SPG11 knockout cognitive and memory deficits and zebrafish motor phenotype rescue with miglustat.
GM2 vesicular accumulation in brain cortex is assessed in SPG11, SPG4, and SPG7 patients to support gangliosides as a therapeutic target.
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