A gene therapy vector comprising an expression cassette coding for a mammalian apolipoprotein E that has a residue other than arginine at at least one of positions 112, 136, or 158, but is not a mammalian apolipoprotein E that has R112, R136 and R158 or a mammalian apolipoprotein E that has C112, R136 and C158, or coding for an antibody that binds to APOE4 or disrupts the binding of APOE to heparan sulfate proteoglycans, and methods of using the vector, are provided.

A gene therapy vector comprising an expression cassette coding for a mammalian apolipoprotein E that has a residue other than arginine at at least one of positions 112, 136, or 158, but is not a mammalian apolipoprotein E that has R112, R136 and R158 or a mammalian apolipoprotein E that has C112, R136 and C158, or coding for an antibody that binds to APOE4 or disrupts the binding of APOE to heparan sulfate proteoglycans, and methods of using the vector, are provided.

The present invention provides a nanodisc with a membrane scaffold protein. The nanodisc includes a membrane scaffold protein, a telodendrimer and a lipid. The membrane scaffold protein can be apolipoprotein. The telodendrimer has the general formula PEG-L-D-(R).sub.n, wherein D is a dendritic polymer; L is a bond or a linker linked to the focal point group of the dendritic polymer; each PEG is a poly(ethylene glycol) polymer, each R is and end group of the dendritic polymer, or and end group with a covalently bound hydrophobic group, hydrophilic group, amphiphilic compound, or drug; and subscript n is an integer from 2 to 20. Cell free methods of making the nanodiscs are also provided.

The present invention provides a nanodisc with a membrane scaffold protein. The nanodisc includes a membrane scaffold protein, a telodendrimer and a lipid. The membrane scaffold protein can be apolipoprotein. The telodendrimer has the general formula PEG-L-D-(R).sub.n, wherein D is a dendritic polymer; L is a bond or a linker linked to the focal point group of the dendritic polymer; each PEG is a poly(ethylene glycol) polymer, each R is and end group of the dendritic polymer, or and end group with a covalently bound hydrophobic group, hydrophilic group, amphiphilic compound, or drug; and subscript n is an integer from 2 to 20. Cell free methods of making the nanodiscs are also provided.

The present invention relates generally to polypeptides or nucleic acids for use in the treatment, management, retardation of progression or normalisation of development of an iduronate-2-sulfatase (IDS) deficiency and/or Mucopolysaccharidosis type II (MPS II) in an individual, wherein the polypeptides comprise iduronate-2-sulfatase (IDS) tethered to a tandem repeat of Apolipoprotein E (ApoEII) or the nucleic acids comprise an iduronate-2-sulfatase (IDS) gene sequence tethered to a tandem repeat of the Apolipoprotein E (ApoEII) gene sequence. The invention also relates to haematopoietic stem and progenitor cells (HSPCs) transduced by such nucleic acids for use in therapies.

The present invention relates generally to polypeptides or nucleic acids for use in the treatment, management, retardation of progression or normalisation of development of an iduronate-2-sulfatase (IDS) deficiency and/or Mucopolysaccharidosis type II (MPS II) in an individual, wherein the polypeptides comprise iduronate-2-sulfatase (IDS) tethered to a tandem repeat of Apolipoprotein E (ApoEII) or the nucleic acids comprise an iduronate-2-sulfatase (IDS) gene sequence tethered to a tandem repeat of the Apolipoprotein E (ApoEII) gene sequence. The invention also relates to haematopoietic stem and progenitor cells (HSPCs) transduced by such nucleic acids for use in therapies.

Compositions and methods for treating rheumatoid arthritis and/or accelerated atherosclerosis are provided, including an inhibitor of oxidized or malondialdehyde-modified low density lipoprotein (LDL) for administration to a subject. Exemplary inhibitors of oxidized LDL include an anti-oxidized LDL antibody, which results in a reduction in the secretion of pro-inflammatory cytokine from primary monocyte in vitro and the plasma cytokine level of inflammatory cytokine in vivo.

The present disclosure provides a genetically modified mouse comprising a genomic nucleic acid encoding human APOE4, a genomic nucleic acid encoding mouse TREM2 modified to include a R47H substitution, and at least one genomic modification selected from the group consisting of: (a) a genomic nucleic acid encoding mouse ABCA7 modified to include an A 1541 G substitution; (b) a genomic nucleic acid encoding mouse APP modified to include G60IR, F606Y, and R609H substitutions; (c) a genomic nucleic acid encoding mouse PLCG2 modified to include a M28L substitution; (d) a genomic nucleic acid encoding mouse MTHFR modified to include a A262V substitution; (e) an inactivated Ceacaml allele; and (f) an inactivated II1rap allele. Methods of producing the genetically modified mouse and methods of using the genetically modified mouse are also provided.

The present disclosure provides a genetically modified mouse comprising a genomic nucleic acid encoding human APOE4, a genomic nucleic acid encoding mouse TREM2 modified to include a R47H substitution, and at least one genomic modification selected from the group consisting of: (a) a genomic nucleic acid encoding mouse ABCA7 modified to include an A 1541 G substitution; (b) a genomic nucleic acid encoding mouse APP modified to include G60IR, F606Y, and R609H substitutions; (c) a genomic nucleic acid encoding mouse PLCG2 modified to include a M28L substitution; (d) a genomic nucleic acid encoding mouse MTHFR modified to include a A262V substitution; (e) an inactivated Ceacaml allele; and (f) an inactivated II1rap allele. Methods of producing the genetically modified mouse and methods of using the genetically modified mouse are also provided.

This application relates to therapeutic siRNA agents and methods of making and using the agents.