Targeting CCR5 as a combination therapy for spinal muscular atrophy

The National Institute of Neurological Disorders and Stroke awarded The Trustees of Columbia University in the City of New York $227,640 on November 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds research investigating CCR5 as a combination therapy target for spinal muscular atrophy (SMA). The project aims to examine whether targeting neuroinflammation—specifically CCR5-dependent neuroimmune signaling in microglia, astrocytes, and neurons—could enhance treatment outcomes for patients with persistent motor deficits despite approved SMN-restoring therapies. Preliminary studies in SMA mouse models indicate that chemokine-mediated CCR5 activation contributes significantly to disease progression, and elevated pro-inflammatory cytokine and chemokine levels in SMA patient cerebrospinal fluid are only partially corrected by current therapies.

Work is performed at Columbia University's Health Sciences Division in New York, New York. The period of performance runs from November 1, 2026, through October 31, 2028. This is a Project Grant, a form of assistance that supports investigator-initiated extramural research.

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the widespread deficiency of the SMN protein. This disease is characterized by the degeneration of motor neurons and synaptic dysfunction across multiple neural circuits that control motor function, leading to severe muscle atrophy and motor impairments. While three SMN-restoring therapies have been approved for SMA, their efficacy is critically dependent on the timing of intervention. Pre-symptomatic treatment offers the greatest benefit, whereas late- stage intervention yields limited recovery. Notably, despite the survival benefit these therapies provide, many patients continue to experience persistent motor deficits. Thus, identifying novel therapeutic targets for combination strategies is essential to improve patient outcomes. This project aims to investigate whether targeting neuroinflammation-an understudied aspect of SMA-could offer a viable strategy for developing combination therapies to better address persistent motor deficits. Emerging evidence suggests that neuroinflammation plays a key pathogenic role in SMA, which could be therapeutically targeted to enhance treatment. In mouse models of SMA, reactive microglia and astrocytes have been shown to contribute to the pathogenic loss of proprioceptive afferent synapses on motor neurons, a key event in motor circuit dysfunction. Furthermore, elevated levels of pro-inflammatory cytokines and chemokines have been found in the cerebrospinal fluid of SMA patients, a signature that is only partially corrected by SMN-restoring therapies. My preliminary studies in SMA mice indicate that chemokine-mediated activation of CCR5-a receptor expressed in microglia, astrocytes, and neurons-plays a significant role in disease progression. Based on these observations, i hypothesize that the CCR5-dependent neuroimmune signaling axis contributes to SMA pathogenesis, and that its inhibition could represent a promising therapeutic approach. The proposed fellowship will allow me to test this hypothesis through a series of well-defined research aims and provide comprehensive training in preclinical translational research to complement my background in neuronal cell biology. In aim 1, i will investigate the effects of CCR5 genetic depletion on motor dysfunction, neurodegeneration, and synaptic integrity in SMA mice. In aim 2, i will assess whether pharmacological blockade of CCR5 with an FDA-approved inhibitor can improve SMA pathology. In aim 3, i will evaluate the potential for combining CCR5 inhibition with AAV9-SMN gene therapy to enhance therapeutic efficacy beyond SMN restoration alone. Successfully achieving these objectives will define the role of CCR5-mediated neuroinflammation in SMA pathology, uncovering new disease mechanisms, and demonstrate the therapeutic potential of CCR5 inhibition as a novel approach to complement SMN-inducing therapies. Ultimately, this work may pave the way for more effective combination therapies to address the unmet needs of SMA patients.