Gene Therapy Recovers Vision in Mice Models of MS, Uncovers How Neuron Connections Are Destroyed

Early research in animal models and human samples reveals how loss of communication between nerve cells contributes to the symptoms of multiple sclerosis (MS), and shows how gene therapy could be used to preserve such connections and protect against vision loss.

Researchers say their work identifies a new approach for developing MS therapies that target nerve cell communication, rather than myelin loss, and could be applicable to other neurodegenerative disorders.

The study, “Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease,” was published in the journal Immunity.

MS is a neurological disease marked by inflammation and a self-attack of the immune system against a person’s brain, spinal cord, and optic nerves.

This attack damages the protective fatty substance covering nerve fibers (axons), which are necessary for proper transmission of nerve signals called myelin. As the myelin sheath is lost (demyelination), the communication between nerve cells is damaged or even interrupted, and nerve cell death occurs, leading to a range of disease symptoms.

Some MS patients experience a version of the disease called progressive MS, in which symptoms continuously worsen over time while their central nervous system (brain and spinal cord) shrinks (atrophies), and the junctions at which nerve cell terminals meet to communicate with each other, called synapses, are lost.

The majority of MS medications work to inhibit the self-attacking immune responses and inflammatory demyelination, but the neurodegenerative aspects of the disease have been more difficult to stop, particularly for patients with progressive MS.

“Most MS research and FDA-approved treatments focus on demyelination and axon death,” Dorothy P. Schafer, PhD, professor at the University of Massachusetts Medical School, said in a press release.

“Far less is known about what happens to the synaptic connections between neurons, which has proven to be a key aspect of neurodegeneration likely leading to cognitive decline in other diseases such as Alzheimer’s disease,” Schafer said.

Using tissue samples from deceased MS patients, a primate model of MS, and mice models of demyelinating disease, Schafer and colleagues investigated how synapses change during MS. They specifically looked at synapses involved in transmitting visual information from the eye to the brain via the optic nerve.

According to the study’s first author, Sebastian Werneburg, PhD, a postdoctoral researcher at Schafer’s lab, the visual system “is an ideal model for investigating MS because it’s easy to access for therapeutic intervention, subtle changes can be readily detected, and the visional pathway is affected in almost half of all patients with the disease.”

Most MS patients experience vision problems at some point, which result from damage to the optic nerve or from lack of coordination in the eye muscle. These problems can be the first indication of the disease.

Similar to other neurodegenerative diseases, researchers found a “profound synaptic loss” in patient samples as a consequence of immune cells called microglia “eating” nerve cell connections.

Microglia are cells that serve as one of the first and main forms of immune defense in the central nervous system, acting to clear cellular debris and dead neurons via phagocytosis — a process by which some cells engulf other cells or particles.

In mice, synapse loss occurred independently of local demyelination and neuronal degeneration, but coincided with a rise in a specific immune factor called C3. C3 is part of the complement system, and is normally not present in the brains of adults. It is produced and activated during demyelinating diseases, but it is not clear why.

As C3 was seen to bind to synapses in models of MS, researchers reasoned this complement protein might be involved with the ongoing destruction of synapses in mice with MS-like disease.

To test this hypothesis, they specifically neutralized C3 at synapses of the visual pathway using gene therapy in mice. The strategy basically worked by delivering genetic material to synapses that provided instructions for the production of a C3 inhibitor.

After injection of the therapy, the inhibitor successfully blocked C3, reduced microglia engulfment, and preserved nerve cell connections, which improved eyesight in mice.

“As a result of this inhibition, we saw improved visional function in mice,” Werneburg said.

Overall, based on the results, the team believes that C3 probably is sending a signal to microglia telling them to eliminate synapses.

The next step will be to determine how C3 turns active during MS and other neurodegenerative diseases.

“It’s possible that therapies targeting different circuits of the brain can be used to protect against synaptic damage in other neurodegenerative diseases such as Alzheimer’s,” Schafer said.