Can a treatment that regenerates damaged nerve cells in mice be adapted to work in humans?

Research details

  • Type of funding: Project Grant
  • Grant Holder: Professor Keith Martin
  • Institute: University of Cambridge
  • Region: East of England
  • Start date: October 2014
  • End Date: March 2018
  • Priority: Treatment
  • Eye Category: Glaucoma


The optic nerve is the specialised cable that sends visual signals from eye to brain. It’s made of retinal ganglion cells. When these cells are damaged – for example, by glaucoma or injury – they don’t repair themselves. This can lead to blindness.

More than 1 in 10 of the 70 million people with glaucoma are blind because treatment came too late or the condition progressed too fast. But only 1 in 10 retinal ganglion cells needs to be working to give useful central vision, so even repairing 1 in 10 cells could save the sight of millions of people.

Optic nerve damage has been repaired in mice using a combination of an injection to stimulate nerve growth and eye inflammation. But this isn’t suitable for humans. The injection only works if together with a specific genetic mutation that the mice were born with.

So in this project the team is tweaking the substance used in the injection so that it can work in normal mice. And they’re working on gene therapy that give adult mice the genetic mutation. They’ll also test the new treatment on human donor tissue and work on minimising side effects.

The work is at an early stage so it may take a long time before this could reach clinical trials but this is a great first step. And in the meantime we may learn more, for example, about how many nerve cells need to be repaired to save a given amount of sight.

  • Scientific summary

    Enhancing optic nerve regeneration in injury and disease models

    Retinal ganglion cells (RGCs) have limited ability to regenerate their axons following injury. However several research groups have recently reported that extensive RGC axon regeneration can be achieved following optic nerve injury in transgenic animals using a combinatorial approach of PTEN and/or SOC3 deletion and inflammatory stimulation.

    It is essential for clinical translation to determine if functional optic nerve regeneration can be achieved in non-transgenic wildtype animals. We will generate an artificial miRNA against PTEN, which will be delivered to RGCs using an AAV viral vector. AAV2/2 is traditionally used to transduce RGCs, however several new serotypes are now available. The team is executing a tropism study to select an AAV serotype that transduces RGCs with high selectivity and efficiency. Using the AAV.miPTEN construct, they are examining whether RGCs can regenerate their axons following optic nerve crush and for the first time in experimental models of glaucoma. Axonal regeneration is being measured using structural outcomes; principally histology to quantify axon regeneration and light sheet fluorescence (LSF) microscopy to visualize regenerated axon projection profiles. Functional measures, including optokinetic head-tracking responses and intrinsic imaging of the visual cortex, will also be tested. Through the use of ex-vivo human retinal explants, they are examining the feasibility of this regeneration approach to stimulate human RGCs axon regeneration. Finally, by generating dominant-negative vectors to knock-down endogenous PTEN and re-express known PTEN recombinant mutant proteins, the are examining downstream signaling mechanisms of PTEN with the aim of developing a more targeted regeneration stimulus with fewer adverse effects.