Spinal Cord Society of Australia

Comments on the latest research publications by Dr Jesse Owens

Dr Jesse Owens, our Senior Scientific Advisor has reviewed the latest SCI publications and has provided the following comment:

 

 

 

Summary - September Report

A recombinant human IgM promotes myelin repair after a single, very low dose.

This paper describes significant increases in myelination in mice whose spinal cords were damaged due to viral infection, toxins, and a pathological autoimmune condition within 5 weeks after the mice were injected with a vanishingly small dose (500 ng) of recombinant monoclonal antibody directed against a specific oligodendrocyte surface antigen

ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans.

This paper provides a cautionary tale. There is now an abundance of literature showing that most of the major inhibitors to axon growth work through receptors that activate a specific intracellular pathway. The first component of this pathway is Rho GTPase. When activated this component leads to the activation of a specific kinase, which in turn leads to cessation of axon growth. This pathway is a point of convergence for both scar and myelin based inhibitors, and would make a nice target for eliminating growth inhibition for axons in the damaged spinal cord. Many studies do indeed show that if either of the major components, of the pathway are prevented from becoming active axons can navigate over inhibitory terrain to a much greater extent than those with this pathway functioning.

This paper demonstrates that in addition to making axons more refractive to inhibition these agents also cause astrocytes to become more reactive to injury and stimulate them to produce a greater quantity of inhibitors. This finding is valuable because it demonstrate the need to develop and employ cell-specific targeting agents that can deliver cargo to specific cell types.

Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia.

Another cautionary story is presented in this paper. The clever and exhaustive work presented here suggests that the survival and differentiation of  bone marrow stromal cells transplanted into the mature CNS may have been seriously misinterpreted in previous studies.

  

This study suggests the current general consensus that bone marrow stem cells are not very immunogenic may be wrong.  Their work indicates that bone marrow cells transplanted into the adult CNS only briefly survive and are unlikely to provide a source of replacement cells for CNS injury or disease. Since this study is contrary to much of the literature to date, we will have to carefully monitor this arena while we consider candidate components to include in a treatment for spinal cord injury in humans.

September Scientific Review

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Summary - August Report

 

Transvascular delivery of small interfering RNA to the central nervous system.

A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. The authors report that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.

Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition.

After a CNS injury in adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Authors show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal.

Nogo enhances the adhesion of olfactory ensheathing cells and inhibits their migration.

 
The migration of olfactory ensheathing cells (OECs) is essential for pioneering the olfactory nerve pathway during development and for promoting axonal regeneration when implanted into the injured central nervous system (CNS). In this study, recombinant Nogo-66 enhanced the adhesion of OECs and inhibited their migration.

Functional motoneurons develop from human neural stem cell transplants in adult rats.

The authors had shown previously that primed human fetal neural stem cells, after transplantation into rat spinal cords, differentiated into cholinergic motoneurons that sent axons to contact medial gastronomies myocytes. HIn this study they demonstrate that (i) axons from the transplanted cells are cholinergic and myelinated, (ii) putative synapses form on transplanted somata and dendrites in the ventral horn, (iii) human fetal neural stem cells transplantation led to normal electromyograms from medial gastrocnemius muscles, and (iv) the gait of transplanted animals was much improved.

 

To read Jesse's comments in full please download the following documents:

Research News and Comment-August 2007

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Will Cafferty who attended our recent Annual Scientific Meeting has published two new papers in the Journal of Neuroscience:

 

Engineering Astrocytes as Injury Repairmen - William B. J. Cafferty, Shih-Hung Yang, Philip J. Duffy, Shuxin Li, and Stephen M. Strittmatter

 

Unfortunately, the CNS throws up a number of roadblocks to axonal regeneration. One of these, chondroitin sulfate proteoglycans (CSPGs), is a major component of the glial scar that forms at the site of a CNS injury. Cafferty et al. exploit the bacterial enzyme chondroitinase ABC (ChABC), which can digest CSPGs, to reopen the roadway. The authors made a transgenic mouse that expressed ChABC in astrocytes under the control of the gfap promoter. After dorsal hemisection of the spinal cord, corticospinal tract axons in wild-type mice stopped abruptly rostral to the lesion. In the transgenic mice, however, axons extended into the lesion, but motor function was not improved. However, after dorsal rhizotomy, axons of sensory neurons grew back through the dorsal root entry zone and into the CNS and also improved sensory function. The next CNS regeneration strategy may be to combine ChABC with targeting of myelin-associated inhibitors.

 

Papers

Cafferty and Strittmatter 2006