Journal Volume 3 - June 2008
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). 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. Our semi-annual Board meetings were held on September 20, 2007 and April 10, 2008.
Project RESTORE at the 2007 Ox Ridge Charity Horse Show
The Ox Ridge Charity Horse Show in Darien is one of Connecticut’s oldest equestrian events. Proceeds from the June 21-24, 2007 event benefited Project RESTORE. Through this event, Christine Fitzgerald Dodge raised over $10,000 in support of TM Research in honor of her sister, Susan Matter.
Project RESTORE Honored at the GPhA Charity Golf Outing
The Generic Pharmaceutical Association (GPhA) served as the host sponsor of the Second Annual Project RESTORE golf classic at Talamore at Oak Terrace in Ambler, PA on September 10, 2007 and raised over $200,000 to benefit The Johns Hopkins Project RESTORE. Our heartfelt gratitude goes out 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, Merchant and Gould, Sutherland Asbill and Brennan LLP.
The Greater Lebanon Valley Lions Club Presented Renewed Vision to Restoring LIFE
On May 4, 2007 Dr. Kerr spoke at the Lantern Lodge Convention Center in Myerstown, Pennsylvania. He provided information about the current status of stem cell research. This year on April 11, 2008 The Greater Lebanon Valley Lions Club hosted an event titled Renewed Vision to Restoring SIGHT in an effort to forge new collaborations in the field of stem cell research. The speakers included Dr. Colin Barnstable of Penn State College of Medicine, Dr. Douglas Kerr of Johns Hopkins University, Dr. Thomas Gardner of Penn State College of Medicine and Dr. Mark Maria of Fava and Maria Eye Associates.
The First UK Transverse Myelitis Conference
On October 13, 2007 the London-based TM Society hosted a one day symposium that included talks from Dr. Douglas Kerr, Dr. Angela Vincent, Dr. Diane Playford and Tony Murphy. The TM Scotland Support Group met on October 17, 2007 with Dr. Kerr and discussed clinical management of these rare diseases and current research updates.
Since its inception, Project RESTORE has raised approximately 2.5 million dollars through philanthropic effort, all of which has been applied to the following scientific initiatives summarized below.
ACCELERATED CURE PROJECT – DATABASE
Johns Hopkins University is the lead center and we have enrolled more than 250 patients in this study. There are more than 1000 patients who have enrolled in this protocol nationwide. Use of the CSF repository has been approved and a project is underway to screen for all known human pathogens (viruses and bacteria) in patients with demyelinating disease. A separate study with a local Maryland company to develop a blood test for MS is also ongoing. Dr. Greenberg chaired a meeting at Cold Spring Harbor in February 2008 with 30 scientists from around the world to discuss the gene-environment interaction in MS.
highlights of Neuro-Imaging Research Studies
We have enrolled over 100 patients and controls and acquired over 200 sessions of data in vivo in the brain and cervical spine using magnetization transfer (MT) and diffusion tensor imaging (DTI). We have also begun preliminary investigations of magnetic resonance spectroscopic imaging (MRS) in the spine. We are currently examining correlations between these metrics with the expanded disability status 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. This study continues to be funded through the generous support of the Shawe family.
We have been the first to show that special MRI techniques, high resolution diffusion tensor imaging (DTI), can be used to define and quantify tissue damage in rats with an animal model of TM (focal EAE). In our study, we found that DTI imaging detected not only pathology at a lesion site within rat spinal cord dorsal column, but also axonal loss and degenerating fibers within the ascending dorsal column fiber tracts related to the lesion. Measures of axonal injury correlated with clinical disability and with histologic injury in rats. The importance of this study is that we now can apply these same measures in humans with TM or MS as a non-invasive biomarker for disease severity.
Optical Coherence Tomography (OCT) - A simple non invasive high resolution technique used to detect changes in the Retinal Nerve Fiber Layer Thickness (RNFL) and Macular Volumes (MV) in an outpatient setting. We hypothesize that RNFL thickness will be a useful tool to quantify axon damage related to optic neuritis (ON) in MS patients, and therefore, will correlate strongly with the ultimate visual outcome 6-12 months later. In addition, we would like to measure the rate of change of RNFL thickness in MS patients with and without history of ON and use it as an early biomarker of permanent visual disability. We are currently enrolling patients with MS, ON and other neuro-inflammatory diseases to assess the RNFL and MV and compare them to age matched controls using OCT. We have scanned about 453 MS, TM and NMO patients and 74 controls. Results show significant decrease in RNFL and MV in MS patients with and without history of ON. Among disease subtypes of MS, progressive MS patients seem to have more marked decrease in both RNFL and MV than Relapsing Remitting MS patients.
Glial Restricted Precursor Stem Cells to Remyelinate Demyelinated Axons in TM
Preclinical Studies: Glial Restricted Precursors (GRPs) are embryonic, lineage-restricted precursors of CNS glial cells and have the potential to differentiate into oligodendrocytes and astrocytes. In rodent demyelinating and injury models, GRP-derived oligodendrocytes remyelinate demyelinated axons, and GRP-derived astrocytes secrete growth factors that stimulate protection and axonal sprouting of damaged axons. We believe the inherent characteristics of GRPs render them a natural means to repair defects in myelin production in the CNS, and thus may be an ideal therapeutic for TM.
Stem cells, including GRPs, can be effectively pre-differentiated prior to transplantation using a variety of agents that we have discovered in a high through-put assay. This pre-differentiation allows the cells, once placed into the highly complex and injurious context of the CNS, to fully differentiate and myelinate host axons. We have also developed a strategy whereby stem cells are engineered to inducibly express a surface molecule that allows them to be delivered by intra-arterial delivery and to escape the circulatory system and migrate into the CNS to initiate repair.
Clinical Studies in Humans with TM: This Will Be A Phase I Single Site, Non-Randomized, Open Label pilot study with dose escalation to obtain preliminary data on the safety and tolerability of glial restricted progenitor (GRP) cells in patients with disability from Transverse Myelitis (TM). We hope to gain FDA approval to begin enrolling for this trial in first quarter 2009. The safety and efficacy data to support this IND are currently being generated.
Motor Neuron Stem Cells: Large Animal Stem Cell Studies
We are currently using large mammals to generate the necessary preclinical data for a clinical trial set to begin in 2011. In this clinical trial, we will transplant infants with the fatal motor neuron disorder Spinal Muscular Atrophy (SMA) with human ES cell-derived motor neurons. Dr. Benjamin Greenberg is leading both the preclinical experiments and the planning for the clinical trial. We have had discussions with the FDA regarding the necessary preclinical data to support this clinical trial. We have decided to initiate these studies with non federally-approved ES cells meaning that we cannot receive federal funding for this research. Since the intellectual property ownership of ES cells remains in legal dispute, corporate investment in ES cell approaches is minimal. While the preclinical studies are underway, we plan to establish the clinical protocol for transplantation, including the patient population, sites of participation, enrollment criteria, surgical approach and outcome measures.
NEUROPROTECTIVE DRUG SCREENING
We are currently initiating a high through-put screen to define novel therapies in neurodegenerative and demyelinating disorders. The goal of this project is to find drugs to treat devastating chronic neurological disease - amyotrophic lateral sclerosis (ALS), and will have utility in other relevant disorders, including childhood motor neuron disease -spinal muscular atrophy (SMA), as well as MS and TM. These disorders have a common injury or involvement of glial cells and/or injury to neurons. Fundamental to this proposal will be the ability to rapidly translate discovery to clinical use through the collaboration of academic labs at Johns Hopkins with biotechnology companies experienced in the various procedural steps required in drug discovery. This academic/commercial partnership will be based on the use of human stem cells to identify new pharmaceuticals and to rapidly bring these drugs to patients.
The proposal is divided into two core projects, based on in vitro cell models, derived from human ES cells, that recapitulate key features or therapeutic targets that are common to the pathophysiology of these diseases. The cell models, injured human motor neurons and glial cells, will be adapted for high through-put screens (HTS). Each project is divided into four common parallel phases. The first phase entails the validation of each stem cell derived cell line for high through-put screening, followed by the second phase using a novel combinatorial drug screen to identify FDA approved candidate neuroprotective drugs that are synergistically effective when used in combination. Lead drug combinations will subsequently be validated in secondary assays and dose optimized. The third phase will examine the pharmacokinetic properties of the lead hits, such as blood brain barrier penetration. The final forth phase will test the biological activity of the candidate drug combinations in relevant disease models. This will involve pre-clinical testing of the identified drugs in disease models (e.g., ALS, EAE or TM mice), to evaluate pharmacokinetics, safety and efficacy (e.g., testing for prolongation of survival). At the end of this proposal, we will be poised to bring candidate drug combinations to clinical trial in several neurological diseases.
Ongoing Clinical Trials
Evaluation of Functional Electrical Stimulation Therapy on Disability and Function in Patients with Primary Progressive and Secondary Progressive Multiple Sclerosis
The Use of Erythropoietin in the Treatment of Acute Transverse Myelitis
This is a Phase I/II randomized, double-blind, placebo controlled, single site pilot study to obtain preliminary data on the safety, tolerability and efficacy of PROCRIT in TM patients. The study will enroll 30 patients over 2 years with a follow-up of 6 months. Patients will be offered entry into the study, if they meet all of the inclusion criteria and none of the exclusion criteria. Patients will be both male and female, aged 18-70 inclusive. Patients who consent to enter the study will be randomized to be given either a subcutaneous dose of 40,000 U PROCRIT (recombinant human erythropoietin) OR placebo. They will receive this therapy within 2 weeks of neurological symptom onset. This will be followed by another dose of 40,000 U PROCRIT or placebo two weeks later. All patients will receive a 5 day course of high dose steroids (1g IV solumedrol qd), which is presently the standard of care, followed by a steroid taper. The primary aim is to obtain preliminary information on the safety of PROCRIT. A secondary outcome measure of the study will be to obtain preliminary data on the change in function using the Expanded Disability Status Scale (EDSS) between baseline, and 6 month follow-up. Another secondary outcome measure will be to obtain preliminary data on the degree of spinal cord axonal loss at 6 months (compared to baseline) as assessed by novel MR imaging (conventional, DTI and MTw).
Research Lumbar Punctures
We have permission to consent patients for research lumbar punctures and plan to bank CSF from PPMS and SPMS patients.
Risk factors for TM study
In an effort to investigate possible causes of Transverse Myelitis, patients diagnosed with idiopathic TM in the last 2 years are recruited for this study. A simple questionnaire mailed to the participant and their medical records are reviewed. Currently over 100 patients are participating in this study.