News Jan 20, 2016
A new study in mice suggests the possibility of one day restoring at least some vision in people blinded by optic nerve damage from glaucoma, a condition estimated to affect more than 4 million Americans, or from trauma.
As reported online scientists from Harvard Medical School and Boston Children’s Hospital restored vision in mice with optic nerve injury by using gene therapy to get the nerves to regenerate and, in a crucial step, by adding a channel-blocking drug to help the nerves conduct impulses from the eye to the brain.
In the future, they believe, the same effect could be achieved with drugs alone.
In the study, previously blind mice turned their heads to follow patterns of moving bars after being given the treatment, said co-senior investigators Zhigang He, HMS professor of neurology at Boston Children’s, and Michela Fagiolini, HMS assistant professor of neurology at Boston Children’s. The technicians doing the tests did not know which mice had been treated.
“By making the bars thinner and thinner, we found that the animals could not only see, but they improved significantly in how well they could see,” said Fagiolini.
Other teams, including one at Boston Children’s, have restored partial vision in mice, but they relied on genetic techniques that can be done only in a lab. Generally, their methods involved deleting or blocking tumor suppressor genes, which encourages regeneration but could also promote cancer.
The new study is the first to restore vision with an approach that could realistically be used in the clinic and that does not interfere with tumor suppressor genes.
Getting nerves to conduct
The key advance in restoring vision was getting the regenerated nerve fibers, or axons, to form working connections with brain cells and also to carry impulses all the way from the eye to the brain.
The challenge was that the fibers regrow without the insulating sheath known as myelin, which helps propagate nerve signals over long distances.
“We found that the regenerated axons are not myelinated and have very poor conduction; the travel speed is not high enough to support vision,” said He. “We needed some way to overcome this issue.”
Turning to the medical literature, they learned that a potassium channel blocker, 4-aminopyridine (4-AP), helps strengthen nerve signals when myelin is absent. The drug is marketed as AMPYRA for multiple sclerosis, which also involves a loss of myelin.
When they added 4-AP, the signals were able to go the distance.
The study used a gene therapy virus called AAV to deliver the growth factors that trigger regeneration (osteopontin, insulin-like growth factor 1 and ciliary neurotrophic factor). Now, He and Fagiolini are testing whether injecting a cocktail of growth factor proteins directly into the eye could be equally effective.
“We’re trying to better understand the mechanisms and how often the proteins would have to be injected,” said He. “The gene therapy virus we used is approved for clinical study in eye disease, but a medication would be even better.”
With regeneration kick-started, 4-AP or a similar drug could then be given systemically to maintain nerve conduction. Because 4-AP has potential side effects including seizures if given chronically, He and Fagiolini have begun testing derivatives, not yet FDA-approved, that are potentially safer for long-term use.
The researchers are further testing the mice to better understand the extent of visual recovery and whether their approach might get myelin to regrow over time.
“The drugs might need to be paired with visual training to facilitate recovery,” said Fagiolini, “but now we have a paradigm to push forward.”
Fengfeng Bei, HMS instructor in neurology, and Hing Cheong (Henry) Lee, HMS research fellow in neurology, who along with He and Fagiolini are members of the F.M. Kirby Neurobiology Center at Boston Children’s, were co-first authors on the paper.
How Environmental Pollutants and Genetics Work Together in Rheumatoid ArthritisNews
It is well known that individuals with a particular version of human leukocyte antigen have an increased risk for rheumatoid arthritis, but there has been growing interest in the role of environmental pollutants. In a new mouse study, researchers probed the relationship between the two.READ MORE
Deficiency of Innate Immune Adaptor TRIF Linked to NeurodegenerationNews
Research has revealed that deficiency of the innate immune adaptor TRIF, which is essential for certain Toll-like receptor signaling cascades, significantly shortened survival time of ALS mice.READ MORE
Comments | 0 ADD COMMENT
World Congress on Advanced Biomaterials and Tissue Engineering
Jun 20 - Jun 21, 2018