Compositions and methods for microglia replacement therapy

Inventors

Bennett, Frederick Christian • Thompson, Peter A. • Bennett, Mariko L. • Jennings, Andy J.

Assignees

Savanna Biotherapeutics Inc • Leland Stanford Junior University

Abstract

The present disclosure provides methods and compositions for microglia replacement therapy in a subject in need thereof. In some cases, the method involves administering myeloid cells to the central nervous system of a subject. In some cases, the myeloid cells are derived from embryonic or extraembryonic tissue. In some cases, the myeloid cells are genetically modified. The genetic modification may include a colony stimulating factor 1 receptor (CSF1R) variant that is resistant to a CSF1R inhibitor, yet retains sensitivity to its ligand (e.g., CSF1, IL34).

Core Innovation

The invention relates to microglia replacement therapy and to engineered myeloid cells intended to differentiate into microglia-like cells in the central nervous system. The approach administers human myeloid cells, including cells derived from embryonic/extraembryonic sources or hematopoietic stem cell or yolk-sac derived sources, and may also use in vitro or ex vivo generated human cells.

A central element is a genetically modified human myeloid cell comprising a nucleic acid encoding a modified human CSF1R protein. The CSF1R protein includes one of specified amino acid substitutions at defined positions in SEQ ID NO:3, including G795A, D796A, T663I, M637L, and G669V, and is described as having reduced sensitivity to CSF1R inhibitors while retaining ligand responsiveness to CSF1 and IL-34.

The disclosed approach further includes a CSF1R-inhibitor-depleted CNS niche for donor engraftment, optional inhibitor sensitivity control using two inhibitors with an on/off control concept, and the selection of CSF1R/IL-34 inhibitors or antagonists, including small molecules or anti-CSF1R antibodies or competitive ligands. The cells are evaluated for microglia biomarker expression and maintenance of signatures that include ApoE not associated with AD, and the document associates the approach with neurological disease applicability including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis.

Claims Coverage

The independent claims cover two main inventive features: a genetically modified human myeloid cell encoding a modified CSF1R protein with one of five specified amino acid substitutions, and a modified human CSF1R polypeptide with the same set of substitutions. The claim coverage is centered on exact CSF1R variant substitutions defined by residue position in SEQ ID NO:3.

The claim set concentrates coverage on CSF1R sequence-defined amino acid substitutions at specific positions in SEQ ID NO:3, implemented either in a genetically modified human myeloid cell or as the modified CSF1R polypeptide itself.

Stated Advantages

Documented Applications