Lysosomal storage disorder biomarkers and methods of use thereof

A method of evaluating the efficacy of a treatment in a subject having an LSD, the method comprising:

• 1) measuring the concentration of a combination of two or more lipids in a sample obtained from the subject after administration of the treatment, wherein the combination of lipids is selected from the group consisting of:
• a) a BMP;
• b) a GM2 ganglioside and/or a GM3 ganglioside;
• c) a GD3;
• d) a GD1a/b;
• and
• e) a GlcCer;
• 2) measuring the concentration of GlcCer in a sample obtained from the subject after administration of the treatment, provided the LSD is an MPS disorder;
• 3) measuring the concentration of Nf-L in a sample obtained from the subject after administration of the treatment;
• and/or
• 4) measuring the concentration of sTREM2 in a sample obtained from the subject after administration of the treatment;
• wherein a decrease in the concentration of the selected lipid(s)/protein(s) in the sample obtained from the subject after administration of the treatment as compared to the concentration of the lipid(s)/protein(s) in a sample obtained from the subject prior to administration of the treatment correlates with treatment efficacy.

A method for treating an LSD in a subject, the method comprising:

• 1) administering an LSD treatment to the subject;
• 2) measuring the concentration of:
• a) a combination of two or more lipids in a sample from the subject, wherein the combination of lipids is selected from the group consisting of:
• i) a BMP;
• ii) a GM2 ganglioside and/or a GM3 ganglioside;
• iii) a GD3;
• iv) a GD1a/b;
• and
• v) a GlcCer;
• b) GlcCer in a sample from the subject, provided the LSD is an MPS disorder;
• c) Nf-L in a sample from the subject;
• and/or
• d) sTREM2 in a sample from the subject;
• and
• 3) adjusting the dosage of the LSD treatment based on the concentration of the selected lipid(s)/protein(s) in the sample from the subject as compared to a control value.

A method of screening a test agent for activity as an LSD treatment, the method comprising:

• 1) contacting a cell with the test agent, wherein the cell has impaired lysosomal storage;
• and
• 2) measuring the concentration of:
• a) a combination of two or more lipids in the cell, wherein the combination of lipids is selected from the group consisting of:
• i) a BMP;
• ii) a GM2 ganglioside and/or a GM3 ganglioside;
• iii) a GD3;
• iv) a GD1a/b;
• and
• v) a GlcCer;
• b) GlcCer in the cell, provided the test agent is screened for activity as an MPS treatment;
• c) Nf-L in the cell;
• and/or
• d) sTREM2 in the cell;
• wherein a decrease in the concentration of the selected lipid(s)/protein(s) in the cell as compared to the concentration of corresponding lipid(s)/protein(s) in a control cell indicates the test agent has activity as an LSD treatment.

A corrected CNS cell comprising reduced accumulation of a metabolic species, wherein a CNS cell comprising a deficiency in a lysosomal enzyme that causes accumulation of the metabolic species within the cell was contacted with a protein comprising:

• (i) a first Fc polypeptide linked to the lysosomal enzyme;
• and
• (ii) a second Fc polypeptide that forms an Fc dimer with the first Fc polypeptide, wherein the protein is capable of binding to the transferrin receptor (TfR),
• to provide the corrected CNS cell comprising the reduced accumulation of the metabolic species.

A method of sorting populations of CNS cells from a tissue sample, comprising:

• (a) contacting the tissue sample with a neuronal marker primary antibody, an astrocyte marker primary antibody, a microglial marker primary antibody, an endothelial marker primary antibody, and an oligodendrocyte marker primary antibody, wherein each primary antibody is uniquely labeled, to provide a labeled tissue sample;
• and
• (b) sorting the cells in the labeled tissue sample by flow cytometry,
• wherein the method provides distinct cell populations of neurons, astrocytes, and microglial cells.