Combining timed GDNF and ChABC gene therapy to promote long‐distance regeneration following ventral root avulsion and repair

Eggers, Ruben; Winter, Fred de; Smit, Lotte; Luimens, Maruelle; Muir, Elizabeth M.; Bradbury, Elizabeth J.; Tannemaat, Martijn R.; Verhaagen, Joost

doi:10.1096/fj.202000559r

Cited by 3 publications

(7 citation statements)

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“…Similarly, although ChABC treatment does not enhance motoneuron survival, our distal ChABC treatment might have been more beneficial when applied more proximally at the reimplantation site (Figure 1E; Eggers et al, 2020). This was shown recently in a study delivering a peptide inhibiting CSPG signaling near the reimplanted nerve root (Li et al, 2015).…”

Section: Gene Therapy Treatment Locationsupporting

confidence: 63%

“…Regulating the duration of GDNF expression, could potentially overcome axonal coil formation. Although coil formation was attenuated significantly in our first study, with only incidental small isolated coils observed (Eggers et al, 2019b), in a second study increased coil formation was observed in 34% of the doxi-GDNF treated animals (Eggers et al, 2020). Between these studies, two differences exist which could underlie the observed coil development in the second study.…”

Section: Gdnf Treatment Concentration and Axonal Coil Formationmentioning

confidence: 50%

“…Inhibitory chondroitin sulfate proteoglycans (CSPG) accumulate throughout the extracellular matrix of the chronically denervated peripheral nerve and form a major obstacle for regenerating axons. Successful digestion of the inhibitory CSPG sidechains occurs in the distal stump using LV-ChABC (Eggers et al, 2020). Despite successful CSPG digestion and a modest electrophysiological improvement after 45 weeks, distal regeneration was not significantly improved after ChABC treatment and GDNF and ChABC do not display synergistic effects.…”

Section: Gdnf Gene Therapy As a Powerful Treatment Strategymentioning

confidence: 97%

“…(ii) Moderate 4 week timed GDNF expression enhanced motoneuron survival and attenuates coil formation (Eggers et al, 2019a,b). (iii) This contrasts higher GDNF expression levels for 4 weeks, which leads to coil formation (Eggers et al, 2020). local infusion therapy (Li et al, 1995;Wu et al, 2003;, suggesting a relationship exists between the duration of GDNF treatment and the degree of motoneuron survival.…”

Section: Gdnf Treatment Timing and Durationmentioning

confidence: 99%

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GDNF Gene Therapy to Repair the Injured Peripheral Nerve

Eggers

Winter

Tannemaat

et al. 2020

Front. Bioeng. Biotechnol.

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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.

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Section: Gene Therapy Treatment Locationsupporting

confidence: 63%

Section: Gdnf Treatment Concentration and Axonal Coil Formationmentioning

confidence: 50%

Section: Gdnf Gene Therapy As a Powerful Treatment Strategymentioning

confidence: 97%

Section: Gdnf Treatment Timing and Durationmentioning

confidence: 99%

See 2 more Smart Citations

GDNF Gene Therapy to Repair the Injured Peripheral Nerve

Eggers

Winter

Tannemaat

et al. 2020

Front. Bioeng. Biotechnol.

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“…This approach, although technically challenging, constitutes an excellent lesion model closely mimicking the clinical situation of patients with brachial plexus injury, where regeneration takes months or even years (Eggers et al, 2019(Eggers et al, , 2020.…”

Section: Sciatic Nerve Injury Performed In Genetically Modified Micementioning

confidence: 99%

Models and methods to study Schwann cells

2022

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Schwann cells (SCs) are the most abundant glial cells of the peripheral nervous system (PNS) (Reed and Feltri, 2021). They were named in honor of the German physiologist Theodor Schwann. Leveraging on his "cell theory" that animals (and plants) are composed by small individual units (i.e., the cells), in the 19th century he described for the first time that peripheral nerves are morphologically complex and composed of many cell types other than neurons. Follow-up studies by Ramon y Cajal, Waller, and Ranvier began to highlight SCs as among the largest and most structurally complex cells in the body, essential during PNS development and capable of remarkably

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Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate

et al. 2023

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Spinal cord injury causes critical loss in motor and sensory function. Ventral root avulsion is an experimental model in which there is the tearing of the ventral (motor) roots from the surface of the spinal cord, resulting in several morphological changes, including motoneuron degeneration and local spinal cord circuitry rearrangements. Therefore, our goal was to test the combination of surgical repair of lesioned roots with a fibrin biopolymer and the pharmacological treatment with dimethyl fumarate, an immunomodulatory drug. Thus, adult female Lewis rats were subjected to unilateral ventral root avulsion of L4–L6 roots followed by repair with fibrin biopolymer and daily treatment with dimethyl fumarate (15 mg/Kg; gavage) for 4 weeks, the survival time post-surgery being 12 weeks; n = 5/group/technique. Treatments were evaluated by immunofluorescence and transmission electron microscopy, morphometry of the sciatic nerve, and motor function recovery. Our results indicate that the combination between fibrin biopolymer and dimethyl fumarate is neuroprotective since most of the synapses apposed to alfa motoneurons were preserved in clusters. Also, nerve sprouting occurred, and the restoration of the ‘g’ ratio and large axon diameter was achieved with the combined treatment. Such parameters were combined with up to 50% of gait recovery, observed by the walking track test. Altogether, our results indicate that combining root restoration with fibrin biopolymer and dimethyl fumarate administration can enhance motoneuron survival and regeneration after proximal lesions.

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Combining timed GDNF and ChABC gene therapy to promote long‐distance regeneration following ventral root avulsion and repair

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 3 publications

References 69 publications

GDNF Gene Therapy to Repair the Injured Peripheral Nerve

GDNF Gene Therapy to Repair the Injured Peripheral Nerve

Models and methods to study Schwann cells

Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate

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