Progress on Optic Nerve Regeneration

The Department of Ophthalmology at the University of Pittsburgh has a specific focus on the optic nerve because it hosts the Louis J. Fox Center for Vision Restoration. Department Chair Dr. José-Alain Sahel said at the June 15 webinar hosted by the Eye & Ear Foundation. This means focusing on the conditions that affect the optic nerve and the ability to regrow and regenerate the optic nerve.

Because the optic nerve is part of the brain, for a long time it was considered impossible to regenerate. Mostly preventative approaches were taken to try and protect the cells from the nerve that originates in the retina. In the last 10-15 years, importance has been placed on being able to keep the connection between the eye and the brain.

The Fox Center hosts a yearly meeting that invites world experts and collaborators from many sister institutions. Brainstorming new areas of research at the clinical level and with scientists has resulted in a very good team that is already paving the way towards new innovative therapies, Dr. Sahel said. They are also working on promising drugs that could help deliver therapies to this region.

“We are very fortunate in Pittsburgh because Stephen Badylak is a world leader in the field of the extracellular matrix,” Dr. Sahel said. One of his lead students has been using his approach on a promising project supported by EEF and donors like Louis J. Fox and the Hillman Foundation to develop a clinically relevant application.

Jordan Chang

Jordan Chang is a third-year medical student who has been working with Stephen Badylak, DVM, PhD, MD, Deputy Director of the McGowan Institute for Regenerative Medicine, for a couple of years now. His part of the presentation was entitled, “Matrix-Bound Nanovesicles Prevent Retinal Ganglion Cell Axon Degeneration and Death.”

Neuro injury results in poor regenerative capability, Chang said. Retinal ganglion cell death is regulated in part by inflammation mediated by microglia and astrocytes.

The extracellular matrix (ECM) provides structural and functional support for tissues and cellular microenvironments. Over 10 million patients have been treated with ECM biomaterials over the past two decades.

“If we can scrape away all of the cells from organs and isolate just the extracellular matrix that has immunomodulatory phenotypes, we will be able to mitigate the inflammation from those cells and promote more of a constructive remodeling as opposed to chronic inflammation,” Chang said.

The good news is the team is well on their way to doing this. They recently identified a unique vesicle in the ECM that they call matrix-bound nanovesicles (MBVs). They are somewhere between 100-300 nanometers in diameter and contain things like proteins and lipids on the surface with immunomodulatory effects. The team has found ways to isolate these vesicles from the ECM. “Importantly, the matrix-bound nanovesicles are able to recapitulate the effects of the whole ECM and move away from inflammation and towards regeneration or constructive remodeling,” Chang said.

Some of the work the team has been working on deals with retinal ganglion cells. A recently published paper from the lab shows that these MBVs can increase axon regeneration or neurite growth.

The Badylak and Kuwajima labs are also collaborating with Wake Forest University on a large animal study with optic nerve crush. Chang was excited about this study and said they are analyzing the first two samples and hope to have results soon.

Optic Nerve Regeneration Lab

Takaaki Kuwajima, PhD, Research Assistant Professor, started four years ago. He was happy to share exciting published and unpublished data. The lab’s goal is to prevent retinal ganglion cell (RGC) death, regenerate the optic nerve, and reconnect the eye to the brain after ocular trauma. The mission is to identify effective and safe drugs and molecules to achieve this goal.

There are no effective drugs or surgeries to prevent optic nerve damage and neuronal death in the eye. After optical injury or spinal cord injury, axons start to degenerate. To identify new molecules and drugs, the lab is focusing on one of the inhibitory molecules for axon regeneration.

In screening 50,000 chemical compounds that overcome inhibition of axon outgrowth, statins were found to be the best candidates. The strongest brand is cerivastatin. “Statins promote axon regeneration after optic nerve crush,” Dr. Kuwajima said. However, a few issues were found:

  • Regenerative ability is still limited
    • RGC protection is weak
    • Cerivastatin is not available in the market because of strong side effects

To overcome these issues, the lab set up a cooperation with Dr. Badylak and Jordan Chang to focus on MBVs. MBV is a critical component of ECM bioscafolds, which changes immune responses and regulates neuron survival and growth. In the mouse model of glaucoma, MBV acts as a neuroprotective reagent.

Several components of ECM are used in clinical therapies. More than 60 are FDA approved and used in clinics. More than eight million patients are treated using ECM bioscafolds. There is a strong possibility that MBV could be approved by the FDA.

The current project is to investigate whether a new combination of Fluvastatin (the second strongest brand and still available on the market) and MBV together can enhance axon regeneration and neuroprotection.

The experimental design is to assess RGC protection and axon regeneration after mouse optic nerve crush.

The combination appears to show a more robust neuroprotective effect as well as a more robust axonal regeneration when compared to either MBV or Fluvastatin alone. Finding that the combination therapy is starting to promote RGC protection and optic nerve regeneration is exciting. Currently, the lab has been investigating molecular mechanism, underlying optic nerve regeneration and neuroprotection by the combination therapy, and hopefully they will provide some exciting new ones.