Summary: A new study reveals gene therapy in combination with neurosurgery can help to improve the rate of survival and promote regeneration of nerve fibers.
Source: KNAW.
Researchers from the Netherlands Institute for Neuroscience (NIN) and the Leiden University Medical Center (LUMC) have shown that treatment using gene therapy leads to a faster recovery after nerve damage. By combining a surgical repair procedure with gene therapy, the survival of nerve cells and regeneration of nerve fibers over a long distance was stimulated for the first time. The discovery, published in the journal Brain, is an important step towards the development of a new treatment for people with nerve damage.
During birth or following a traffic accident, nerves in the neck can be torn out of the spinal cord. As a result, these patients lose their arm function, and are unable to perform daily activities such as drinking a cup of coffee. Currently, surgical repair is the only available treatment for patients suffering this kind of nerve damage. “After surgery, nerve fibers have to bridge many centimeters before reaching the muscles and nerve cells from which new fibers need to regenerate are lost in large numbers. Most regenerating nerve fiber do not reach the muscles. The recovery of arm function is therefore disappointing and incomplete,” explains researcher Ruben Eggers of the NIN.
Combination of treatments
By combining neurosurgical repair with gene therapy in rats, many of the dying nerve cells can be rescued and nerve fiber growth in the direction of the muscle can be stimulated.
In this study, the researchers used regulatable gene therapy with a growth factor that could be switched on and off by using a widely used antibiotic. “Because we were able to switch off the gene therapy when the growth factor was no longer needed, the regeneration of new nerve fibers towards the muscles was improved considerably,” says Ruben Eggers.
A stealth gene switch
To overcome the problem of the immune system recognizing and removing the gene switch, the researchers developed a hidden version, a so-called ‘stealth switch’. Professor Joost Verhaagen (NIN) explains: “The stealth gene switch is an important step forward towards the development of gene therapy for nerve damage. The use of a stealth switch improves the gene therapy rendering it even safer.”
The gene therapy is not yet ready for use in patients. While the ability to switch off a therapeutic gene is a large step forward, the researchers still found small amounts of the active gene when the switch was turned off. Therefore, further research is needed to optimize this therapy.
Funding: The research was funded by Wings for Life, the International Spinal Research Trust and a donation from the Dwarslaesiefonds.
Source: Joost Verhaagen – KNAW
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration” by Ruben Eggers, Fred de Winter, Stefan A Hoyng, Rob C Hoeben, Martijn J A Malessy, Martijn R Tannemaat, and Joost Verhaagen in Brain. Published January 18 2019.
doi:10.1093/brain/awy340
[cbtabs][cbtab title=”MLA”]KNAW”Gene Therapy Promotes Nerve Regeneration.” NeuroscienceNews. NeuroscienceNews, 18 January 2019.
<https://neurosciencenews.com/gene-therapy-nerve-regeneration-10583/>.[/cbtab][cbtab title=”APA”]KNAW(2019, January 18). Gene Therapy Promotes Nerve Regeneration. NeuroscienceNews. Retrieved January 18, 2019 from https://neurosciencenews.com/gene-therapy-nerve-regeneration-10583/[/cbtab][cbtab title=”Chicago”]KNAW”Gene Therapy Promotes Nerve Regeneration.” https://neurosciencenews.com/gene-therapy-nerve-regeneration-10583/ (accessed January 18, 2019).[/cbtab][/cbtabs]
Abstract
Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration
Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.
