Project Summary Spinal bulbar muscular atrophy (SBMA) exhibits mitochondrial abnormalities. We and other investigators have shown that mitochondrial dysfunction in SBMA involves both loss and gain of function from the mutant androgen receptor (AR), acting as a critical driver to motor neuron (MN) degeneration. The proposed project aims to implement mitochondrial transfer to treat SBMA MNs. Our specific aims for this project will be as follows. In Specific Aim 1, we will develop an isogenic human neural stem cell (NSC) model, consisting of isogenic control, disease, and AR knockout lines. We will isolate extracellular vesicles (EVs) secreted from different isogenic NSC lines and specify biological characteristics of these vesicles for new biomarker identification. In Specific Aim 2, we will culture disease MNs by supplementing mitochondrial EVs derived from the isogenic control NSCs. We will examine the EV uptake potential of disease MNs, track the intracellular fate of transferred mitochondria in recipient neurons, and evaluate whether EV-mediated mitochondrial transfer will attenuate SBMA pathology. This project will establish the rationale and validate the feasibility of mitochondrial transfer as a novel neuron-type-specific therapeutic intervention for SBMA and other related neurodegenerative and neurologic disorders.