Monoclonal Antibody Against CXCL13 to Promote Axonal Plasticity, Regeneration, and Functional Recovery After Spinal Cord Injury: A Translational Opportunity
Abstract
Following spinal cord injury (SCI) highly damaged axons degenerate, while surviving fibers are unable to regenerate and have a limited plasticity and capacity to sprout and to re-establish lost connections. This largely contributes to functional neurological impairment and permanent severe disability. Experimental evidence suggests that providing a favorable glial and extracellular environment, along with the activation of the limited intrinsic potential of neurons to sprout and regenerate, may lead to the best results in terms of functional recovery. Classical molecular screening strategies, studies of neurological development as well as of regenerative organisms or models after axonal injuries, have contributed to progress in improving plasticity and repair after SCI. However, they have so far failed to provide transformative solutions for the cure of clinical SCI. There is therefore an urgent need to identify alternative strategies with a translational potential that enhance repair and recovery after SCI. This proposal aims to investigate a novel regenerative and pro-plasticity strategy that we have recently identified. This consists of an antibody-based treatment against a molecule called CXCL13, which is responsible for the recruitment of immune cells that restrict neuroplasticity and regeneration. In pilot studies, my laboratory found that the antibody reduces inflammation and is able to enhance neuronal plasticity and recovery after experimental SCI. This proposal will be investigating the full potential of this treatment in plasticity, axonal regeneration, and functional recovery after SCI in the mouse. We will also investigate the fundamental mechanisms underpinning the phenotype, including its potential to affect the extra-neuronal spinal environment. There is still poor understanding of how the immune system controls the ability of the nervous system to mount a repair and regenerative response after injury. This proposal will contribute to bridge this knowledge gap by providing research that clarifies how immune cells and the nervous system communicate in the context of SCI. Ultimately, these studies have the goal to offer novel understanding and to propose novel targets and strategies that can be used to promote repair and recovery after SCI. Before this research can be translated to clinical SCI, work in the 3-year funding period will establish the impact of the anti-CXCL13 antibody on enhancing the plasticity and regeneration of nerve fibers and on the recovery of neurological function in animals following SCI. This treatment aims to improve neurological disability in over 2.5 million patients worldwide, about 250,000 to 300,000 individuals in the United States, across lifespan from young adolescents to seniors, in the society at large as well as in the military. This proposal will also investigate potential risks associated with the use of the antibody that are mainly related to alteration in the immune response. However, this antibody has already been used successfully in other preclinical models of human disease such as neuroinflammation. Since this treatment promises to be safe and is suitable for humans as well as rodents, once careful experimentation has been completed in animals at the end of this funding period, it has the potential to be translated to humans to foster regeneration and recovery of function in a relatively short time span, estimated at approximately 5 years after pre-clinical work is completed. The specific clinical benefits will include improvement in sensory and motor functions that will contribute to the amelioration in the quality of life of both affected individuals and families by reducing the need for care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110747
Entities
People
- Simone Di Giovanni
Organizations
- Imperial College London
- United States Army