The therapeutic small molecule can restore visual functions after optic nerve injury



Traumatic injuries to the brain, spinal cord and optic nerve in the central nervous system are the leading cause of disability and the second leading cause of death worldwide. CNS injuries often result in catastrophic loss of sensory, motor, and visual functions, which is the most challenging problem faced by clinicians and research scientists. Neuroscientists from the City University of Hong Kong (CityU) recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual functions after optic nerve injury, providing great hope for patients with optic nerve injury, such as vision loss associated with glaucoma.

There is currently no effective treatment for traumatic injuries to the central nervous system, so there is an immediate need for a potential drug to promote CNS repair and to achieve full recovery of functions, such as visual function, in patients.”


Dr. Eddie Ma Chi-Leh, co-chair and associate professor in the Department of Neuroscience and director of the Laboratory Animal Research Unit at CityU

Enhancing mitochondrial dynamics and motility is central to successful axonal regeneration

Axons, cable-like structures that extend from nerve cells (neurons), are responsible for transmitting signals between nerve cells and from the brain to muscles and glands. The first step to successful axonal regeneration is the formation of active growth cones and activation of the regrowth programme, which involves the synthesis and transport of materials for axonal regrowth. These are all energy-demanding processes, which require active transport of the mitochondria (the power center of the cell) to the injured axons at the distal end.

Injured neurons therefore face special challenges requiring long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, since in adults axonal mitochondria are mostly static and local energy intake is critical for axonal regeneration.

A research team led by Dr. Ma has identified a small therapeutic molecule, M1, that can increase mitochondrial fusion and motility, leading to long and sustained axon regeneration. Regenerated axons triggered neural activities in target brain regions and visual functions were restored within four to six weeks after optic nerve injury in M1-treated mice.

The small molecule M1 enhances mitochondrial dynamics and maintains long-distance axon regeneration

Photoreceptors in the eyes [retina] Sending visual information to neurons in the retina. To facilitate the recovery of visual function after injury, axons of neurons through the optic nerve must regenerate and relay nerve impulses to visual targets in the brain via the optic nerve for image processing and formation,” explained Dr Ma.

To investigate whether M1 can promote long-distance axonal regeneration after CNS injuries, the research team evaluated the extent of axonal regeneration in M1-treated mice four weeks after injury. Strikingly, most of the regenerated axons of M1-treated mice reached up to 4 mm distal to the crush site (i.e., near the optic chiasm), while no regenerated axons were found in vehicle-treated control mice. In mice treated with M1, survival of retinal ganglion cells (the nerve cells that transmit visual stimuli from the eye to the brain) increased significantly from 19% to 33% four weeks after the optic nerve injury.

This indicates that M1 treatment maintains axon regeneration over long distances from the optic chiasm, that is, midway between the eye and the target brain region, to multiple subcortical visual targets in the brain. Regenerating axons induce neural activities in the target brain regions and restore visual functions after M1 treatment.”

M1 treatment restores visual function

To further explore whether M1 treatment can restore visual function, the research team gave M1-treated mice a pupillary reflex test six weeks after the optic nerve injury. They found that the eyes of M1-treated mice restored the pupillary constriction response upon blue light illumination to a level similar to that of uninjured eyes, indicating that M1 treatment could restore the pupillary constriction response after optic nerve injuries.

In addition, the research team evaluated the response of rats to a looming stimulus — a visually induced innate defensive response to avoid predators. Rats were placed in an open chamber with a shelter in the form of a triangular prism and a rapidly expanding black overhead circle as a looming stimulus, and their freezing and flight behaviors were observed. Half of the mice treated with M1 responded to stimulation by hiding in a shelter, demonstrating that M1 induced robust axonal regeneration to re-nerve visual target brain regions under the cortex for the full restoration of their visual function.

Potential clinical application of M1 for nervous system injury repair

The seven-year study highlights the potential of a readily available non-viral treatment for central nervous system repair, which builds on the team’s previous research on peripheral nerve regeneration using gene therapy.

“This time we used the small molecule, M1, to repair the central nervous system simply by injecting it inside the bottle into the eye, which is a well-established medical procedure for patients, for example to treat macular degeneration. The successful restoration of visual functions, such as the pupillary reflex and pupillary reflex,” said Dr. Ou Ngan Ban, Research Associate in the Department of Neuroscience, The response to visual stimuli with a looming sight was observed in mice treated with M1 four to six weeks after optic nerve damage.

The team is also developing an animal model to treat vision loss associated with glaucoma using M1 and possibly other common eye diseases and visual impairments such as diabetic retinopathy, macular degeneration and traumatic optic neuropathy. Thus, further investigation is warranted to evaluate the potential clinical application of M1. “This research breakthrough holds promise for a new approach that can address unmet medical needs in accelerating functional recovery in a limited treatment time frame after CNS injuries,” said Dr. Ma.

The results have been published in the international scientific journal Proceedings of the National Academy of Sciences (PNAS)M1 small molecule promotes optic nerve regeneration to restore target-specific neuronal activity and visual function.

Dr Au and Dr Ma are the first author and corresponding author respectively of the paper. Another collaborator is Dr. Vincent Ku-chi-chiu, Associate Professor in the Department of Chemistry at CityU. The research was funded by CityU and the Hong Kong Research Grants Council.

Source:

Journal reference:

Au, NPB, et al. (2022) The small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function. PNAS. doi.org/10.1073/pnas.2121273119.



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