Non-human mammal model of human degenerative disorder, uses thereof, and method of treating human degenerative disorder

Inventors

Goldman, Steven A.

Assignees

University of Rochester

Abstract

The present application relates to a non-human mammal model of a human neurodegenerative disorder, methods of producing the non-human mammal model, and methods of using the non-human mammal model to identify agents suitable for treating a neurodegenerative disorder. The present application also relates to methods of treating neurodegenerative disorders and restoring normal brain interstitial potassium levels.

Core Innovation

The invention describes a non-human mammal model of human neurodegenerative disorders using engraftment and replacement of host glia with human, disease-specific glial cells. Human glial chimeras are produced by administering human disease-specific glial progenitor cells, including astrocyte-biased hGPCs, into forebrain/brain stem regions of the model, with achievement of a specified proportion of human glia in regions including the corpus callosum/white matter.

The model is used to study therapeutic effect by administering candidate agents to the chimeric model and assessing outcomes related to disease phenotypes. Huntington’s disease-focused example findings are described using HD glial chimeras containing mutant HTT-expressing hGPCs, which show impaired motor learning and altered medium spiny neuron physiology, including hyperexcitability and altered input resistance and altered spontaneous and evoked responses such as EPSPs.

The invention further reports that engraftment with normal glia slows disease progression and extends survival in R6/2 mice, and it normalizes elevated interstitial K+ levels in the HD striatum. A mechanistic framing is provided that dysregulated glial K+ channel function and defective K+ handling relate to elevated interstitial K+ and neuronal excitability, supporting a therapeutic concept of restoring normal brain interstitial potassium levels through glial progenitor administration.

Claims Coverage

The document includes one independent claim with multiple dependent claims that add specific constraints to the subject selection, the administered glial progenitor preparation, and certain anatomical and cellular details. The independent claim is centered on restoring normal brain interstitial K+ levels by administering a CD140a+ and CD44+ glial progenitor cell preparation to a subject with dysregulated glial K+ channel function.

Taken together, the claimed approach requires selecting a subject with dysregulated glial K+ channel function and administering a preparation of CD140a+ and CD44+ glial progenitor cells at an effective dosage to restore normal brain interstitial glial K+ levels. The dependent claims further characterize the dysregulation and specify phenotype, including astrocyte-biased and/or A2B5+, with additional narrowing to striatum and to a human-targeted context as reflected in the partial content.

Stated Advantages

Documented Applications