Optic Nerve Regeneration Research


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FOCUSED RESEARCH 

It is the intention of this program to raise investment capital to accelerate research into the regeneration of the human optic nerve.  The researchers at The Schepens have enjoyed some success in regenerating the optic nerve in mice.

Studies on pathogenesis, regeneration and repair of optic nerve atrophy/optic neuropathy

Introduction:

The sight-robbing effects of optic nerve atrophy are due to the loss of the retinal cells that make up the optic nerve. Unfortunately, human eyes do not have the ability to regenerate the optic nerve following injury, and therefore the resultant loss of sight is permanent. Due to considerable scientific progress in the recent past, we now understand a great deal about the complex organization of the visual system, we have important clues as to why neural regeneration fails, and we can generate credible strategies for promoting regeneration and initiating repair of the mature central nervous system. 

The optic nerve is the largest sensory tract of the human central nervous system. It connects the eye with the visual centers of the brain by way of approximately 1.2 million separate axons from an identical number of retinal ganglion cells. The organization of these fibers and the synaptic connections they form with targets in the brain are critical for creating and maintaining an accurate topographic map of the visual world. 

We wish to develop successful means of repairing the optic nerve, drawing upon a wide range of emerging technologies, including tissue engineering, stem cell biology, genetic engineering, and recombinant growth factors. The combined application of these technologies provides a promising approach to restoring useful visual communication between the eye and the brain.

Background:

Optic nerve atrophy is a blinding disorder that results from pathologic processes within the optic nerve itself, or among the retinal ganglion cells whose axons comprise the optic nerve. Direct damage to the optic nerve can be caused by ischemia (partial to complete cessation of blood through the vessels of the optic nerve, inflammation (sometimes associated with multiple sclerosis, or with inflammatory disorders of other arteries of the head), traction as the nerve fibers pass through the lamina cribrosa (often as a complication of high-tension glaucoma), gliosis of the lamina cribrosa, or trauma (partial to complete severance of the nerve). In some cases, no obvious cause is identified. Indirect damage to the optic nerve occurs when the retinal ganglion cells degenerate during the course of intraocular diseases, especially glaucoma. While increased intraocular pressure is a risk factor for the optic neuropathy of glaucoma, pressure alone cannot explain the loss of ganglion cells. Moreover, loss of ganglion cells due to a direct assault is accompanied by loss of ganglion cells adjacent to the originally damaged cells, a “sympathetic” process that can be reversed by strategies that promote “neuroprotection”.  Since optic nerve atrophy is typically the consequence of a prolonged pathologic process, attempts to “treat” the disease as it progresses must, on the one hand, replenish and replace damaged cells, and, on the other hand, do so in a pathologic microenvironment. Therefore, understanding the nature of the primary pathologic processes is necessary, first, as a means of preventing further deterioration of the nerve, and, second, so that treatment has maximum potential for success. 

Research at The Schepens Eye Research Institute addresses some of the pathogenic processes that lead to retinal ganglion cell loss and optic nerve atrophy, and probes novel strategies for replenishing retinal ganglion cells and promoting optic nerve regrowth. The faculty of The Institute fully subscribes to the Institute’s stated mission – to bring knowledge gained through laboratory and clinical research to successful application in the clinic in order to prevent blindness and restore sight to those who are visually impaired.

OPTIC NERVE REGENERATION AND REPAIR RESEARCH AT THE SCHEPENS  

Current Projects now being pursued with existing extramural grant support.

            The following experimental research projects are already in progress at The Schepens, funded largely from grants from the National Institutes of Health, although other sources are also contributing. The rate of progress for each of these projects is subject to meaningful acceleration if significant additional funding is made available. Additional funding would make it possible for the principal investigators (listed in parentheses) to recruit of new post-doctoral fellows and additional technical support, to purchase certain items of instrumentation, and to purchase additional supplies. The individual projects are grouped according to the primary research thrust of the projects.

 

Pathogenic processes that lead to ganglion cell loss and optic neuropathy

 

1.            Protect ganglion cells, damaged by crush injury of optic nerve, from dying and promote outgrowth of new nerve fibers toward the brain target structures by over-expressing genes for molecules that inhibit apoptosis and promote neurite outgrowth. (Chen)

 

2.            Determine the role of inflammation and immunity in promoting the degeneration of retinal ganglion cells and optic nerve in a mouse model of pigment dispersion, high tension glaucoma. (Streilein, Mo)

 

3.            Determine the role of active TGFb-2 in promoting gliosis of the optic nerve (a) as it passes through the lamina cribrosa/scleral outlet, and (b) at the site of optic nerve injury secondary to trauma, ischemia or inflammation, and develop strategies for inhibiting this process by inhibiting effects of TGFb. (Taylor, Streilein)

 

4.            Determine the role of activated microglia in the pathogenesis of glial scars that develop following injury/ischemia of the optic nerve, and define mechanisms to alter microglia behavior in the direction of suppressing scar formation (Streilein,Ng,Taylor)

 

Strategies to promote regeneration of optic nerves

 

5.            Identification of growth inhibitors produced from adult uninjured, as well as injured, brain astrocytes, so that inhibitors of these inhibitors could be identified/generated so that optic nerve growth could be promoted. (Chen)

 

6.            Implant polymers impregnated with select growth factors, anti-oxidants, and/or anti-apoptotic (anti suicide) factors that are designed to be delivered in a time-sustained fashion that is necessary for rescue of degenerating ganglion cells and for promoting neuroprotection and neurite outgrowth. (Young, collaborators).

 

7.            Develop miniaturized assays for neurite outgrowth using high-throughput screening. Screening is done via a robotic workstation approach, and compounds discovered by this approach are tested in vivo on appropriate models of optic nerve injury/atrophy. Using this technique, we can quickly assay the effect of over 5,000 small molecules in a variety of concentrations and combinations. These substances are all known to be safe and orally tolerated, and could rapidly lead to new drug therapies for optic neuropathy. (Young, Chen, collaborators)


8.            Develop a gene delivery method that will enable the introduction of genes, such as Bcl-2, into retinal ganglion cells to prevent death by apoptosis, etc. (Chen, Kazlauskas).

 

Strategies to replace cells necessary for optic nerve regeneration

 

9.            Isolate mature ganglion cells from post-natal retina, and implant these cells into the vitreous cavity of eyes with ganglion cells damaged by experimental injury to the optic nerve (Chen)

 

10.            Implant neural stem cells into the vitreous cavity of mice with pigment dispersion glaucoma to determine whether they can replenish ganglion cells and form axonal projections to targets in the brain. Determine where progeny of the stem cells migrate, and what phenotypes they adopt. (Young, Ng)

 

11.            Create biopolymer/stem cell composites that, when implanted into the vitreous cavity, will allow stem cells to differentiate into ganglion cells, forming nerve fibers that reach targets in the lower brain – superior colliculus, lateral geniculate body. (Young)

 

 

 

New Projects that can be created by additional full support

 

            The projects described below have been planned and anticipated by scientists currently at The Schepens, but have yet to be initiated because of the lack of funding availability. A source of funding would make it possible for the principal investigators (listed in parentheses) to recruit of junior faculty members, as well as post-doctoral fellows and technical support, to purchase items of instrumentation needed to launch new research protocols, and to purchase the requisite supplies.

 

Pathogenic processes that lead to ganglion cell loss and optic neuropathy

 

12.            Examine the potential pathogenic relationships between non-arteritic anterior ischemic optic neuropathy and aberrations in blood vascular supply to the optic nerve head and the nerve (D’Amore).

 

Strategies to promote regeneration of optic nerves

 

13.            Determine the extent to which (a) restoration of a normal intraocular immunosuppressive microenvironment, or (b) provision of exogenous anti-inflammatory/immunosuppressive factors is important in (a) protecting ganglion cells and the optic nerve from degeneration and atrophy in mouse model of pigment dispersion glaucoma, and (b) promoting acceptance of implanted stem cells. (Streilein, Mo, Young).

 

14.            Clinical trial to study a long-standing mood stabilizer, lithium, for its neuroprotective and regenerative effects on ganglion cells in patients with glaucoma and optic nerve degeneration. (Chen, collaborator).

           


Strategies to replace cells necessary for optic nerve regeneration

 

15.            Implant neural stem cells (unmanipulated or genetically altered to secrete select growth factors) into the vitreous cavity of eyes of mice with pigment dispersion glaucoma, analyzing for neuroprotection that retards rate of ganglion cell loss. (Young)

 

16.            Create biopolymers (extension of research initiated above, #11) containing stem cells that will build upon established techniques using peripheral nerve bridges to restore connections between retina and brain, and will promote topographical innervation of target structures in the brain (superior colliculus, etc) that are essential for restoration of vision. (Young, collaborators)

 

Early diagnosis and drug discovery

 

17.            Develop non-invasive methods, including electrophysiologic, for early diagnosis of optic nerve damage and degeneration, as well as detection and measurement of regeneration and functional repair of visual pathways following institution of experimental therapies. (Chen, Young, collaborators – murine systems; Elsner, Hirose – human system)

 

18.            Discover small molecules that will promote optic nerve regeneration. This requires, on the one hand, the development of miniature assays for neurite outgrowth using high-throughput screening to select for compounds that promote neurite outgrowth (see  #7 above), and, on the other hand, development of delivery systems that will bring these drugs to the retina, the optic nerve, the optic projections, and the optic targets in the brain. (Chen, Young)

 

Schepens Scientists Participating in Optic Nerve Regeneration Research Programs

 

Dong Feng Chen, Ph.D., Asst Professor

Andrius Kazlauskas, Ph.D., Asso. Professor

Michael Young, Ph.D., Asst Professor

Tat Fong Ng, Ph.D., Instructor

J. Wayne Streilein, M.D., Professor

Jun Song Mo, M.D., Ph.D., Instructor

Andrew W. Taylor, Ph.D., Asst. Professor

Patricia D’Amore, Ph.D., Professor

Ann Elsner, Ph.D., Asso. Professor

Tatsuo Hirose, M.D., Professor