Scientist shows gene therapy protection of eyesight in models of MS

January 23, 2020
New research reveals the molecular process in which synaptic connections in the brain are damaged in multiple sclerosis and how this contributes to neurodegenerative symptoms. The study also shows how gene therapy may be used to preserve neural circuits and protect against vision loss in the disease. The findings suggest a path for developing therapies that may protect synapses from the damaging effects of MS and could be broadly applicable to other neurodegenerative disorders.

Vision loss is one of the most common symptoms of MS and is often one of the first that patients notice. Problems with vision result from damage to the optic nerve that connects the eye to the brain or from lack of coordination in the eye muscle.

Profound synaptic loss was observed in animal models as microglia engulfed and eliminated presynaptic connections. Microglia are the immune cells of the central nervous system and are emerging as key players in regulating neural circuit structure in health and disease. One of the vast number of functions microglia perform in the brain is similar to the role macrophages perform in the immune system: clearing cellular decay and dead neurons from tissue.

Researchers found the protein C3 in abundance at synapses. C3 is not normally found in adult brain tissue. C3 protein usually only shows up in neural tissue during the developmental stages of the brain when synapses are being pruned. Synaptic pruning eliminates weak or unused synapsis as the brain matures to help efficiency and conserve energy.

In the case of demyelinating disease, it is not known why C3 is being produced and activated. This complement protein binds to synapses, sending the signal to microglia that the otherwise healthy-seeming synapse should be eliminated. This leads microglia to attack synapses.

Researchers at the University of Massachusetts Medical School used a gene therapy approach and adeno-associated virus to deliver Crry, an inhibitor of C3, specifically to synapses in the visual system while leaving the rest of the brain untouched, to see if synapses could be spared and vision preserved. Crry is a natural inhibitor of complement proteins such as C3. These regulators help protect cells or tissue from attack by the immune system. After injection of the AAV into the circuit, Crry localized to synapses and successfully preserved them by binding to C3 so microglia couldn't damage them. As a result of this inhibition, researchers saw improved visional function in mice.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the study’s authors said the protective effects of the AAV-delivered inhibitor were specific to the visual circuit. The next step for researchers will be to determine how the C3 protein is being activated and produced during MS.

The study was published in Immunity.

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