The Johns Hopkins Project RESTORE was founded in August 2004 as a multidisciplinary clinical and research effort to develop new basic research and clinical therapies in multiple sclerosis (MS) and transverse myelitis (TM).  RESTORE evolved out of the separate MS and TM Centers at Hopkins and links basic science with clinical research and clinical care and allows researchers to share resources and effort in developing new approaches to diagnose and treat neuroimmunologic disorders.  The Johns Hopkins leadership of this program includes Dr. Peter Calabresi, Director of the MS Center, and Dr. Douglas Kerr, Director of the TM Center.  Chitra Krishnan is the Executive Director and oversees the clinical, research, education and fundraising efforts of Project RESTORE. 

To help achieve the goals of Project RESTORE, we have a Board of Ambassadors whose members include leaders from all areas of professional endeavor, including grateful patients.  The Chairman of the Board is Mr. Bruce Downey, CEO and President of Barr Pharmaceuticals, Inc., Vice- Chair is Mrs. Cindy McLean from Atlanta, GA.  The Transverse Myelitis Association and The Cody Unser First Step Foundation are also on our Board of Ambassadors represented by Sandy Siegel, Cody and Shelley Unser. The Board holds semi-annual meetings where it discusses and advises Ms. Krishnan and the rest of the scientific team about RESTORE activities.  The Board is asked as one of its primary responsibilities to direct and participate in fundraising for RESTORE activities. 

SCIENTIFIC UPDATE

Since its inception, Project RESTORE has raised approximately 1.5 million dollars through philanthropic effort, all of which has been applied to the following scientific initiatives summarized below.

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

• Based on our initial research findings on the role of IL-6 as an important biomarker of TM involved in the neural injury of TM, which was published in The Journal of Clinical Investigation, research is now underway to examine the immune cell types that are involved in the up regulation of IL-6 production by astrocytes in the CNS and to explore the different pro-inflammatory cytokines produced by immune cells that regulate IL-6 production. Our preliminary data suggest that IL-6 production from peripheral immune cells is the most potent inducer of CNS astrocyte IL-6.
• In studies to define the upstream ‘triggering’ events in autoimmunity, IL-17 is known to be a critical mediator of disease by regulating other cytokines known to stimulate IL-6 production.  Our data suggests that IL-17 and IL-6 production from peripheral blood mononuclear cells in TM and early MS is increased and may induce astrocyte IL-6 production through another cytokine, IL-1β.

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) to define neuroprotective strategies and novel immunologic therapies (i.e. Kv1.3, FLT3)

Animal models of TM

• We continue to study animal models of TM caused by immune cells moving into the spinal cord and using IL-6 that causes spinal cord degeneration

Animal model of NMO

• We are creating an animal model of NMO (Devic’s disease) in order to understand the pathogenic features of NMO-IgG and other contributors

Mechanisms of neurodegeneration

• We have learned how axon structure and function is supported by glial cells (myelin-producing cells).
• We have developed a cell culture model of CNS myelination and are exploring the fundamental consequences of demyelination and inflammation
• 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

• Dr. Carlos Pardo continues to characterize abnormalities in the brain and spinal fluid of patients in which neuroinflammatory reactions are involved.  Novel proteomics-based approaches for studying multiple proteins in fluids and tissues from patients with neuroinflammatory disorders such as MS, TM, epilepsy and autism are being tested.  We are currently correlating these findings with imaging and clinical outcomes in patients with autism, Rasmussen's encephalitis, MS and TM. This project has been made possible through Mrs. Sharon Umphenour’s philanthropic gift.
• In a recent study published in the Annals of Neurology, Dr. Calabresi and his team have identified voltage gated potassium channels on immune cells and have suggested that targeting these channels may be a promising therapeutic target in MS.  These channels are expressed on a special type of immune cell called the dendritic cell (DC), which is responsible for activating the T cells in MS and other autoimmune conditions, thus, impacting the disease course.  Although, more functional studies need to be performed to confirm this, this work holds promise as a novel way of modulating the immune response in MS, affecting the course of immune cell reactivation and infliction of damage in the brain.
• We have recently identified a key enzyme released by activated T cells that causes damage to the nerves – Granzyme B. 

High dose Cytoxan in aggressive MS

• This is an ongoing human clinical trial in aggressive MS that may induce long term remission.
• To date, we have spoken with or discussed the study with more than 50 patients who expressed an initial interest in the study, and have enrolled 9 patients into the trial. Three patients have completed 2 years in the study. 
• No patients had serious side effects
• All patients except one either improved or remained stable with no further relapses.

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.  We have continued to further understand the downstream signaling pathway to further dissect how myelin proteins communicate with the axon.  It is hoped that by understanding how myelin proteins are neuroprotective, it could lead to novel approaches to therapeutic interventions for rare neuroimmunologic 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, 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.  We have further found high expression of FLT3 in MS brain tissue, and we continue to understand when and how this receptor is turned on during inflammation.

Neuro-Imaging
We have made tremendous progress in enrolling patients in the imaging clinical trial.  The goal of this study is to correlate magnetic resonance spectroscopic imaging (MRS), magnetization transfer imaging (MT), and diffusion tensor imaging (DTI) 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.  To date, we have enrolled 55 patients into this study.  Preliminary data has revealed that this imaging technique can detect cord disease in MS and is more strongly correlated with clinical status than a measure of atrophy.

Neuroregeneration
Our research work on the potential of embryonic stem cell–derived motor neurons to functionally replace those cells destroyed in paralyzed adult rats was recently published in the Annals of Neurology (Ann Neurol 2006; 60: 32–44).  We have shown that restoration of functional motor units by embryonic stem cells is possible and represents a potential therapeutic strategy for patients with paralysis. This is the first report of the anatomical and functional replacement of a motor neuron circuit within the adult mammalian host using a unique combination of growth factors to attract transplanted embryonic stem cell–derived axons toward skeletal muscle targets.

FUNDRAISING EVENTS

A number of successful fundraising and awareness events were held during the past year. 

The First Annual Project RESTORE Charity Golf Outing sponsored by The Boys Entertainment
The Dellwood Country Club in Rockland County, NY was the venue for the First Annual Project RESTORE Charity Golf Outing Sponsored by The Boys Entertainment on June 19, 2006.  More than 140 golfers played at the event which was followed by a star-studded silent auction, attended by Allan Houston, Kurt Thomas, Rodney Hampton, Herb Williams and others. The event raised about $100,000 for research on rare neuroimmunologic disorders, such as MS and TM.  Our heartfelt gratitude to Scott Harrison, his partners, Richie Felder and Dean Kapneck, and all of the staff at The Boys Entertainment.

Project RESTORE at the 2006 OX Ridge Charity Horse Show
At the Ox Ridge Charity Horse Show in Darien, CT from June 16th to June 18th, 2006, Christine Fitzgerald-Dodge and Serendipity Equestrian Products raised funds and awareness for Project RESTORE by sponsoring a booth and a silent auction.  Congratulations Christine on a fantastic fund raiser and awareness campaign!

Project RESTORE Honored at the GPhA Charity Golf Outing
The Generic Pharmaceutical Association - GPhA - served as the host sponsor of a golf tournament at Tournament Players Club at Avenel in Potomac, Maryland on September 18, 2006 that raised nearly $200,000 to benefit The Johns Hopkins Project RESTORE. Our heartfelt gratitude to all of the generous donors, sponsors and volunteers for their support.  Eagle sponsors included Barr Laboratories, Mylan Laboratories, and Teva Pharmaceuticals.  Birdie sponsors included Williams and Connolly LLP and Winston and Strawn LLP.  Par sponsors included Actavis, Kirkland and Ellis LLP, and Sutherland Asbill & Brennan LLP.

Project RESTORE 5K Family Walk/Run
October 15th, 2006 in New Canaan, CT, friends, family, well-wishers and supporters gathered for the first annual Project RESTORE 5K walk.  RESTORE Ambassadors Bob and Robin Lord spearheaded this event to celebrate Bob’s recovery and to raise awareness.  The event raised well over $20,000! Organizing this event was a huge endeavor and the Lords were supported by Bob’s sister, Nancy, and all his family and friends, Dr. Peter Hasapis and Dr. James Slater from the New Canaan Medical Group, Dr. Amy Knorr -- Neurology Associates of Norwalk and aQuantive (Avenue A | Razorfish). 

FUTURE GOALS

Our financial goal for the next year is to raise $3.2 million dollars which will support the following:

Three research fellows (training physicians) to train in the Division of Neuroimmunology both in basic science and clinical research ($300,000)

Endowment of $1 million dollars to fund certain projects and personnel in perpetuity

Nursing/clinical coordinator personnel to carry out clinical trials ($200,000)

$500,000 for myelinating and paralysis stem cell projects

$250,000 for imaging MRI projects

$200,000 for proteomics/diagnostic projects

$250,000 for neuroprotection projects

$500,000 for center equipment/microscopy