Scientific Update from Project RESTORE
Peter Calabresi, M.D., Douglas Kerr, M.D., Ph.D., Chitra Krishnan, M.H.S.

Project RESTORE at Johns Hopkins strives to restore hope, restore function and restore the lives of patients and families suffering with transverse myelitis and multiple sclerosis.  This project funds researchers to work together to discover new biological indicators of neuroimmunologic diseases, develop new imaging strategies, and conduct clinical trials to support the creation of progressive treatments.  The Project RESTORE team is actively engaged in many exciting studies and we continue to make significant strides in our research.   What follows is a brief summary of some of the research currently being conducted.  Please visit our web site for additional information on these projects and other work being carried out at the Johns Hopkins Project
RESTORE.

http://www.hopkinsneuro.org/restore/

Neuro-Imaging
We have acquired preliminary human in vivo data using magnetic resonance spectroscopic imaging (MRS), magnetization transfer imaging (MT), and diffusion tensor imaging (DTI).  We are currently enrolling patients in a trial to correlate these metrics with the expanded disability scale (EDSS) and multiple sclerosis functional composite (MSFC) to assess the predictive and concurrent validity of these.  The aim of this study is to classify individuals based on measures of disability, characterize their walking patterns, in order to detect specific kinematic deficits, and use this information to direct future rehabilitative strategies.  We predict that impairments of spasticity and ataxia seen in MS can be used as functional indices of damage to specific spinal cord pathways that leads to measurable differences in walking patterns. 

Biomarkers of TM/MS are necessary to define disease subgroups and response to therapy

Our research paper on the role of IL-6 as an important biomarker of TM involved in the neural injury of TM has been published in The Journal of Clinical Investigation.

Further studies are underway to define the upstream ‘triggering’ events in autoimmunity. Preliminary evidence suggests that certain cytokines, namely IL-17, IL-23 and IL-12, participate in the initiating events of autoimmunity in TM and perhaps other autoimmune disorders. 

Animal models are required to model human disease to develop new therapies:

Animal model of MS:

• We have utilized an established model of MS (termed EAE)

Animal models of TM:

• We have created an animal model of TM caused by immune cells moving into the spinal cord
• We have created an animal model of TM in which IL-6 causes spinal cord degeneration.

Mechanisms of neurodegeneration

• We have learned how axon structure and function is supported by glial cells (myelin-producing cells).
• We are beginning to understand how to protect axons in the absence of glial cells.
• We have learned how other glial cells (microglia) can injure neurons.
• We have established a model in which we can study the direct damaging effects of T cells to nerve cells.

Inflammatory mechanisms of
neurodegeneration
Through the generous funding of Ms. Sharon Umphenour, Dr. Pardo has commenced upon a project to define the inflammatory abnormalities in the brain and spinal fluid of patients with inflammatory degeneration.  Dr. Pardo is correlating inflammation, as defined by novel proteomics-based approaches, with imaging and clinical outcomes in patients with autism, Rasmussen’s encephalitis, MS and TM.  

High dose Cytoxan in aggressive MS
This is an ongoing human clinical trial in aggressive MS that may induce long term remission.

We have enrolled and completed this therapy in 8 patients

• No patients had serious side effects
• Most patients either improved or remained stable

Neuroprotection
We have recently discovered that one of the myelin associated proteins induces a protective pathway preventing nerve fibers and axons from degeneration.  Moreover, we have found a novel receptor on axons that mediates this protective pathway.  It is hoped that this will result in the discovery of a novel class of therapeutic compounds for neurodegenerative diseases.

Innate Autoimmunity
Autoimmune diseases often result from inappropriate or unregulated activation of autoreactive T cells. Traditional approaches to treatment of autoimmune diseases through immunosuppression have focused on direct inhibition of T cells. However, one line of investigation that we have recently completed is to inhibit the innate autoimmune cells that initiate the T cell response.  This work, recently published in the Proceedings of the National Academy of Sciences, showed that inhibition of the FLT3 (CD135) receptor resulted in markedly attenuated “MS” in an animal model.  This work, using small molecule inhibitors of receptor function, suggests a potential mechanism for treating autoimmune diseases.

Neuroregeneration
Embryonic stem cell-derived motor neurons can be induced to survive in the adult, rodent host and to extend axons out from the spinal cord.

These axons form functional connections with host muscle, allowing paralyzed rats to recover from paralysis.