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CMCC 2343

Chelation of zinc promotes nerve regeneration within the central nervous system

Inventors: Zhen Huang, Larry Benowitz, Paul Rosenberg, David Lippard, Yiqing Li

Invention Types: Therapeutics

Research Areas: Neurology/Neuroscience

Keywords: CNS, Neuropathy, New Indication/Use, Polymer, Small Molecule/Drug, Spinal Cord Injury, Stroke, Target

For More Information Contact:  Caron, Connie

 

Invention Description:

Following traumatic nerve injury, ischemic damage, or degenerative diseases such as glaucoma, projection neurons of the eye--the retinal ganglion cells (RGCs)--cannot regrow their axons and soon begin to die, leaving patients with lifelong visual losses. Past research has shown ways to activate RGCs’ intrinsic growth capacity and counteract extracellular signals that normally inhibit axon growth in animal models. However, these methods do not fully arrest the slow loss of RGCs that persists after axonal injury, the cells that partially regenerate their axons are likely to be in a compromised state, and the overall number of regenerating axons is low. The present invention concerns novel ways to both suppress cell death and strongly enhance the regeneration of injured axons.


Drs. Larry Benowitz and Paul Rosenberg have discovered that there is a rapid elevation of free zinc in the retina after the optic nerve has been injured, and that this zinc strongly inhibits neuronal survival and the regrowth of axons in an optic nerve injury model. Mitigating this elevation in free zinc by chelation promotes regeneration of injured axons. Investigating the downstream mechanisms of these phenomena has led to the identification of multiple molecular targets that play a key role in both the survival and the regeneration pathways in response to free zinc. Furthermore, drugs that interact with these targets have similar effects to zinc chelation on both survival and regeneration.


The inventors envision an implantable device, or other means of delivering the therapeutic formulation, such as nanoparticles, for promoting regeneration in a lesioned nerve or tract within the central nervous system. Along these lines, the inventors have been collaborating with another Boston Children’s lab to develop a slow-release polymer to deliver a highly selective zinc chelator over the critical time window needed to maintain RGC survival and promote axon regeneration.


These findings can be applied therapeutically, alone and in combination with other approaches, to disorders and diseases of the CNS caused by axonal injury such as spinal cord trauma, optic nerve injury, glaucoma, multiple sclerosis, and stroke.

Applications:

• Novel treatment to improve the survival of injured neurons and promote the regeneration of injured nerve fibers, primarily but not exclusively those located within the eye. |

• Therapeutic delivery modalities to repair neural connections using these treatments. |

• Potential to repurpose existing drugs to treat nerve damage.

Competitive Advantages:

• Potential to regrow axons in the optic nerve, or spinal cord, which to date have only been able to partially regenerate. |

• Potential to be applied across the CNS. |

• Potential for delivery to specific injured neurons.

Business Opportunity:

Exclusive or non-exclusive license

Key Publications: 1. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Li Y, Andereggen L, Yuki K, et al. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2): E209-E218. doi: 10.1073/pnas.1616811114. |

2. Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury. Trakhtenberg EF, Li Y, Feng Q, et al. Exp Neurol. 2018 Feb;300:22-29. doi: 10.1016/j.expneurol.2017.10.025.

IPStatus: Pat. Pend.