Help us: Donate
Follow us on:
×

Menu

Back

Gene Therapy Improves Motor Function in Aged Mice

Image of someone editing DNAImage of someone editing DNA

A gene therapy treatment can ameliorate the loss of motor function and muscle strength in old mice, offering elderly people hope for continuing their active lives.

DOK7 is crucial for muscle function

Declining motor function is common with aging and can significantly reduce the quality of life. This decline occurs at least in part due to changes in neuromuscular junctions, the synapses that connect nerves to muscles. Studies have found increased denervation at neuromuscular junctions with aging and in sarcopenia. Therefore, researchers chose these junctions as a therapeutic target to treat age-related motor dysfunction.

The DOK7 gene is required for normal development of neuromuscular junctions; mutation of DOK7 causes a neuromuscular disease. Several years ago, a team of researchers in Japan used gene therapy to introduce a working copy of DOK7 into mice with a mutated version. The intervention improved the motor activity of the mutant mice and increased their lifespan.

Making mighty mice

Now, the team is using the same approach to see if DOK7 therapy can improve motor function in aged mice [1]. The therapy uses a recombinant muscle-tropic adeno-associated virus (AAV) as a vector to deliver a wild-type version of the human DOK7 gene to aged male mice. Male mice of the strain used in these experiments normally begin to exhibit changes in their neuromuscular junctions and experience decreased motor function when they are 24 months old, and they usually die when they’re between 24 and 32 months old.

The team injected the mice with the DOK7 therapy vector (AAV-D7) when they were 24 months old and carried out tests four months later. They found that AAV-D7 treatment enlarged the neuromuscular junctions of the mice and suppressed denervation. In fact, they report that the treated 28-month-old mice had lower levels of denervation than untreated 24-month-old mice, suggesting that AAV-D7 not only prevents denervation but even promotes reinnervation.

To find out if the restored neuromuscular junctions rescued motor function, the team subjected the mice to motor performance tests. One test measured how long a mouse could stay on a rotating rod, and a second test measured the twitch force of a hind limb muscle upon direct stimulation. The AAV-D7 treated mice did better on both tests than sham-treated mice did, showing that the therapy improved motor function and muscle strength.

Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

Conclusion

This is exciting work. It’s wonderful to imagine that, with a single injection, we could avoid the motor problems we associate with growing old. That said, gene therapies have a mixed track record, so long-term safety trials would be crucial, and before that, researchers need to show that the treatment works in human cells. The paper notes that there are only a handful of studies reporting the effects of age on neuromuscular junctions in humans, and their results aren’t entirely consistent. Therefore, the first step towards an eventual therapy for people must be to better understand how human neuromuscular junctions change with age.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

Castration Influences Growth and Median Lifespan in Mice

Research published in Aging Cell has discovered that castrated male mice show similarities to females in growth and lifespan [1]....

Michael Lustgarten Fights Back Against Microbes

Dr. Michael Lustgarten delivers a clear and enlightening exploration of the intricate relationship between microbial burden and aging in Microbial...

Stabilized Vitamin C Improves Brain Aging in Mice

Korean scientists publishing in Nature were able to increase the stability of vitamin C, a powerful antioxidant, using a short,...

Bryan Johnson Thinks AI Should Run Your Life

In this video, Bryan Johnson, founder and CEO of Blueprint, shared his ideas about the role of artificial intelligence (AI)...

Literature

  1. Ueta, R., Sugita, S., Minegishi, Y., Shimotoyodome, A., Ota, N., Ogiso, N., Eguchi, T., and Yamanashi, Y., (2020) DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice. iScience, doi: 10.1016/j.isci.2020.101385
About the author

Sedeer el-Showk

Sedeer became a professional science writer after finishing a degree in biology. He also writes poetry and sff, and somehow juggles an ever-growing list of hobbies from programming to knitting to gardening. Eternal curiosity and good fortune have taken him to many parts of the world, but he’s settled in Helsinki, Finland for the moment. He hopes he’ll never stop learning new things.
No Comments
Write a comment:

*

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.