Optic Nerve Regeneration Research


Home

 

 

Dr. Larry Benowitz.

Department of Neurosurgery

Children's Hospital, Boston, Massachusetts.


 

Dr. Larry Benowitz has a new website.  http://www.childrenshospital.org/research/benowitzlab/

We are in contact with Dr. Larry Benowitz.  It is our intention to create a not-for-profit 501 3c organization to be used to direct funds to the research programs headed by Dr. Benowitz.  This anticipated focused research is briefly described in a quote from a recent communication from Dr. Benowitz to a research group in Scotland which has been conducting stem cell research.

"Our lab has been investigating ways to stimulate retinal ganglion cells to regenerate injured axons into the optic nerve. Although such regenerative growth does not take place under normal conditions, we discovered that it can be stimulated to occur, at least partially, by inducing an inflammatory reaction in the eye. We discovered that macrophages secrete a 14 kDa protein which, in conjunction with the carbohydrate mannose (which is constitutively present in the eye), enables injured retinal ganglion cells to survive axotomy and regenerate their axons for considerable distances into the normally inhibitory optic nerve environment. This regeneration can be enhanced greatly if we also transfect retinal ganglion cells with a gene expressing a dominant-negative form of a receptor that normally responds to inhibitory signals emanating from myelin-associated proteins. References for our recent studies are given below.

We are starting to think about using stem cells to replace retinal ganglion cells that have been lost – no one has yet found a way to get stem cells to differentiate into retinal ganglion cells that can then grow axons into the optic nerve. We believe that this will require pre-implantation treatments to get the progenitors to the appropriate stage where they can become retinal ganglion cells per se (using strategies similar to those being discovered by the Jessell Lab at Columbia for motor neurons); then using strategies similar to those we are currently using to coax reti


 

October 4th, 2004.

THE FOLLOWING PAPER HAS JUST BEEN PUBLISHED BY DR.BENOWITZ AND HIS RESEARCH COLLEAGUES.

Switching Mature Retinal Ganglion Cells to a Robust Growth State In Vivo; Gene Expression and Synergy with RhoA Inactivation. (16 pages)

To access this paper, which is a PDF file, please doubleclick the following hyperlink:

images\optic nerve research, Oct. 4, 2004.pdf

September 3, 2004

THE FOLLOWING PAPER HAS BEEN ACCEPTED FOR THE JOURNAL OF NEUROSCIENCE.

Switching Mature Retinal Ganglion Cells to a Robust Growth State In Vivo; Gene Expression and Synergy with RhoA Inactivation. (62 pages)

To access this paper, which is a PDF file, please doubleclick the following hyperlink:

images\optic nerve research, Sept. 3, 2004.pdf

 

THE FOLLOWING PAPER WAS PRESENTED AT THE INTERNATIONAL SYMPOSIUM ON DEVELOPMENTAL NEUROSCIENCE IN EDINBURGH, SCOTLAND, AUGUST 3 - 7TH, 2004.

 

Axon regeneration in the mature CNS:
extrinsic signals and intracellular signaling pathways
 

L.I. Benowitz, Y. Yin, D. Fischer, N. Irwin

 Children’s Hospital (Boston) and Harvard Medical School, Boston MA, USA

 

As in other parts of the mature CNS, retinal ganglion cells (RGCs) do not normally regenerate injured axons, and soon undergo apoptosis. However, by stimulating an inflammatory reaction in the eye, many RGCs survive axotomy and regenerate axons into the inhibitory optic nerve environment. In dissociated cultures, we found that this regeneration is stimulated by a 14 kDa protein that is secreted by macrophages (MDP14), acting in combination with the carbohydrate mannose, which is constitutively present in the eye, and requiring elevated intracellular cAMP. When delivered together with cAMP analogs into the vitreous, MDP14 stimulates optic nerve regeneration in vivo. The profile of gene expression induced by these factors was investigated in RGCs isolated via fluorescent-activated cell sorting. Whereas axotomy alters the expression of numerous genes, macrophage-derived factors stimulate the expression of a relatively small number of additional genes, including GAP-43, SPRR1A, and several transcription factors, that transform RGCs into a regenerative state. The intracellular transduction pathway leading to these changes involves a purine-sensitive protein kinase that we have identified. In vivo, activation of this kinase with inosine promotes the growth of new brain connections and improves functional outcome after a cortical stroke. Finally, we show that axon regeneration can be enhanced further with gene therapy. We have used AAV to transfect RGCs with a dominant-negative form of NgR (NgRdn), a receptor that mediates the inhibitory effects of 3 myelin proteins (MAG, NogoA, OMgp). NgRdn expression increased regeneration dramatically when RGCs were in a growth-activated state, but not otherwise. In contrast, overexpression of wild-type NgR prevented RGCs from regenerating axons. These studies point to novel ways of inducing axon regeneration in the CNS, and demonstrate that successful regeneration will probably require both activation of neurons’ intrinsic growth state and overcoming inhibitory signals.

 

To access this paper, please doubleclick the following hyperlink.

images\Fischer et al.pdf