Investigating the Repair Ability and Mechanisms of Combinatorial Pharmacological and Biomaterial-Based Intervention After Experimental Spinal Cord Injury
Abstract
Following spinal cord injury (SCI), highly damaged axons degenerate, while surviving fibers are unable to regenerate 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 a combinatorial pharmacological and biomaterial- based intervention after experimental spinal cord injury. In recent studies, my laboratory found that activating the gene expression potential of neurons with a small molecule called TTK21 is helpful to promote growth. Our collaborator, Dr. Stupp, has also shown that the use of biomaterials can promote neuronal growth after experimental spinal cord injury. Therefore, here we will combine the two strategies to maximize regrowth of neurons and promote recovery of neurological function. We will also investigate the fundamental mechanisms underpinning the phenotype by using high spatial resolution techniques that will allow to identify the cells and signals that interact with injured neurons in the spinal environment. In fact, there is still poor understanding of how the interaction between cells in the spinal cord with injured axons control the ability of the nervous system to mount a repair and regenerative response after injury. Ultimately, these studies have the goal to offer a novel therapeutic strategy and to propose novel targets to promote repair and recovery after SCI. Before this research can be translated to clinical SCI, work in the 3 years funding period will establish the impact of the combinatorial pharmacological and biomaterial-based intervention 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, including about 250 to 300,000 individuals in the U.S. across a life span from young adolescents to seniors, in the civil society at large as well as in the military. This proposal will also investigate potential risks associated with the combinatorial use of the pharmacological and biomaterial interventions. However, their individual use has already been used successfully and safely in preclinical models of SCI. 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 in approximately 5 years after preclinical 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
- Jan 04, 2024
- Source ID
- HT94252310721
Entities
People
- Simone Di Giovanni
Organizations
- Imperial College London
- United States Army