Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease

Area of Science:

• Neuroscience
• Genetics
• Regenerative Medicine

Background:

• Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3, is a fatal neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene.
• Current treatments for MJD are lacking, and while mesenchymal stromal cells (MSCs) show promise, patient regression necessitates further investigation into optimal therapeutic strategies.

Purpose of the Study:

• To compare the efficacy of single intracranial versus repeated systemic MSC administration in alleviating MJD phenotypes in severe genetic rodent models.
• To identify potential neurospectroscopic biomarkers correlating with MJD treatment outcomes.

Main Methods:

• Utilized two severe genetic rodent models of Machado-Joseph disease.
• Administered mesenchymal stromal cells (MSCs) via single intracranial injection and repeated systemic administration.
• Assessed motor behavior, neuropathology, and metabolite levels (GABA, glutamate, Myo-inositol) using neurospectroscopy.

Main Results:

• A single MSC transplantation provided only transient effects in MJD models.
• Periodic systemic MSC administration resulted in sustained improvements in motor function and neuropathology.
• MSC treatment increased GABA and glutamate levels while decreasing Myo-inositol, correlating with motor improvements.

Conclusions:

• Repeated systemic MSC administration represents a more effective therapeutic strategy for Machado-Joseph disease than single injections.
• Neurospectroscopic biomarkers like GABA, glutamate, and Myo-inositol may indicate disease status and treatment efficacy in MJD.
• Findings support the redesign of MSC therapies for sustained benefits in MJD and other polyglutamine disorders.