GDNF Gene Therapy to Repair the Injured Peripheral Nerve

Abstract

A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks ( Koliatsos et al., 1994 ). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival ( Chai et al., 2000 ). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy.

A novel mechanism for the formation and propagation of neural tumors and lesions through neural highways

“…We have identified novel neural highways that drive the neural and perineural spread of peripheral nerve tumors/ lesions. The three overarching systems of neural highways discussed here demonstrate the role of the nervous system as an underlying delivery system (Eggers et al, 2020). These complex interconnections underscore the intricate anatomy of the neurologic system.…”

Efficient Targeted Transgene Delivery to Injured Lower Motor Neurons

“…Future studies will evaluate delayed AAV vector delivery to transected motoneurons, as delays of only a few days between nerve crush injury and exposure to adenovirus vector yields decreased transduction e ciency [81]. Lastly, while we demonstrate e cient and robust transduction of facial motor neurons using this approach, it will be important to test therapeutic transgene candidates such as glial derived neurotrophic factor in order to advance this technology towards clinical application [28,43].…”

“…FDA-approval has already been granted for two AAV-based gene therapies, one for treatment of lower motor neuron disease (onasemnogene abeparvovec for spinal muscular atrophy) [39][40][41]. Animal models suggest gene therapy may improve peripheral nerve regeneration and functional outcomes [28,[42][43][44]. Clinical translation of gene therapy for nerve repair, though, requires preclinical evidence of targeted transduction of transected axons relevant to peripheral nerve injuries.…”

GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries

“…A root avulsion injury is seen in traffic accidents and complicated childbirths. It consists of spinal roots being severed from the spinal cord, and as a consequence, motor neurons die, and peripheral nerves deteriorate (Ruven et al, 2018;Eggers et al, 2020). Ruven and colleagues (2018) used the root avulsion model combined with a 2-week delayed root reimplantation to test the effectiveness of GDNF treatment along with fetal lumbar cell transplantation on motor neuron death and muscle atrophy prevention.…”

“…These nerves are considered the most fragile structure in our body due to the ease of getting damaged by crush, compression, and trauma (Hussain et al, 2020). Peripheral nerve injuries (PNIs) can occur due to trauma, complicated childbirth, and tumor extirpation (Eggers et al, 2020;Fadia et al, 2020;Li et al, 2020). PNIs resulting from trauma are responsible for approximately 5% of patients admitted to a Level I trauma facility in the USA, costing around 150 billion US dollars in health-related costs per year (Taylor et al, 2008).…”