Research Areas

Below you will find a description of our research plan based on the goals of Project RESTORE.

Improve the diagnosis and treatment of patients with MS and TM
As centers of excellence in two related neuroimmunologic diseases, our first goal is to work towards developing a better understanding of the natural history of these diseases, thereby diagnosing and treating patients accurately and efficiently. Generating and sustaining clinical databases for MS and for TM respectively is an important focus of Project RESTORE.

Database development and maintenance: To better understand the natural history of diseases such as transverse myelitis and multiple sclerosis, clinical databases are essential to define subgroups of patients and to identify clinical features that predict response to therapy and guide the development of clinical trials. We are the only center in existence with a complete database on all TM patients that includes blood, spinal fluid and tissue samples for future analysis. We have a large repository of CSF samples on MS patients, but much work remains to be done to further develop and maintain this database and to link it to critical clinical variables that will be followed in emerging trials.

These databases are complex and require sophisticated data analysis to extract critical clinical clues. Maintenance of these databases requires two full- time data managers.

To develop novel diagnostic strategies to define pathologic features in MS and TM patients
An important research endeavor in many disease entities has been the development of better and novel diagnostic strategies in the form of non-invasive imaging, biomarkers and neuronal markers of injury. These markers are critical as objective measures of outcome in designing clinical trials.

Development of novel imaging strategies: To better define the pathology and subtypes of TM and MS, we must develop novel imaging strategies for patients. Although conventional MRI approaches effectively define abnormal regions within the nervous system, they do not precisely define what that abnormality is. Emerging technologies allow a more precise understanding of pathology in the nervous system and can identify appropriate therapeutic interventions in the phase during which those interventions are likely to be helpful.

Proteomics to develop biomarkers: The past decade has seen much research focused on gene expression arrays that have identified several novel transcripts in MS brain tissue. Proteomics is a relatively newer field that holds significant promise for identifying individual proteins or patterns of proteins that are involved in MS. Johns Hopkins Medicine has a large proteomics facility that includes several mass spectroscopy units, gas chromatography, HPLC, and a dedicated bioinformatics unit. This facility has been further coupled with laser capture microscopy and thus has the ability to work with complex biological material to identify unique proteins, peptides, lipids, or carbohydrate moieties expressed in pathological tissues and fluids. Additionally, the Johns Hopkins Medicine MS center has acquired a Ciphergen proteomics machine (SELDI mass spectroscopy) that is capable of screening large numbers of clinical serum and CSF MS samples to screen for patterns of aberrant protein expression. This project has already been initiated and thus will be operative during years 1-5 of the project.

Develop Immunologic Therapies that Block Neurologic Injury
In order to develop novel immunologic therapies that stop injury to the brain and spinal cord, the first step is to define why the immune system goes awry and what happens when the immune system crosses into the central nervous system. These studies need to be translated from the laboratory to animal models of MS and TM.

Definition of immune derangements and neural injury pathways: The main goal of these studies is to identify immune factors that directly or indirectly mediate neuronal/axonal damage in the CNS, and investigate in vivo (within an animal system) neural consequences of inflammatory and non-inflammatory demyelination.

Identification of the neural consequences of immune effector cells utilizing a human neuronal, neuronal/glial and neuronal/glial/immune cell co-culture system are other important studies towards understand neural injury pathways.

Animal model development: A first step to confirm if the model of injury created in vitro (outside an animal system) hold true in vivo is to develop an animal model that is similar to the disease that develops in humans. By understanding what the immune derangements and the triggers are, we can further the development of an animal model. Animal models hold great promise in studying new therapies prior to the development of clinical trials.

Restore Function to Patients Through the Development of Restorative Therapies
Animal stem cell experiments: We continue to focus on generating motor neurons from embryonic stem cells, and have recently shown that we can generate thousands of new motor neurons in the spinal cords of paralyzed animals. Further, at Johns Hopkins, we have learned how to stimulate these motor neurons to extend axons out toward muscle. A critical goal of restorative therapies is to rewire the nervous system. Specifically, motor neurons must extend their axons (‘wires’) to connect to muscle. We must learn how to appropriately direct these axons in order to generate functional recovery. We have not yet defined the biological principles that guide all of these areas. This will be the focus of the next three years. It is unclear how quickly these findings will be applied to paralyzed patients. In the current environment, a significant proportion of stem cell research is not allowed and funded by the federal government.

Clinical trials in neurorestoration: The spinal cord is not “programmed” to regenerate after injury. It is an evolutionary trade-off that we have very complex neural systems, yet unlike lower animals, we cannot recover function after injury. The first step is to develop a strategy to “reprogram” the nervous system so that it can regenerate and define how to generate spinal motoneurons from embryonic stem cells. This will enable transplantation studies in animals which will further enable the development of clinical trials for these neurorestorative therapies in humans. We are unsure when clinical trials with neurorestorative therapies will commence.

Facilitate the Rapid Translation of Discoveries to New Therapies
In order to facilitate rapid translation of discoveries to new therapies, their efficacy has to be demonstrated in animal models of the disease followed by safety studies and clinical trials in humans. Much of this also requires the use of efficient equipment and technology to monitor the progress of, for example, cytokine levels, during drug therapy.

Animal drug trials: The main purpose of this project is to lay the groundwork for clinical studies investigating interventions for autoimmune demyelinating conditions of the central nervous system. Based on our research on the pathogenesis of TM and MS, we have now uncovered a critical pathway relevant to the understanding of the pathophysiologic mechanism that leads to tissue injury in TM and MS. Our goal is to further this understanding with in vitro and in vivo studies in rodent models of TM and MS and other autoimmune diseases, while studying the role of therapeutic interventions by dose response studies of drugs such as thalidomide, erythropoietin and statins. The ultimate objective of this research project is to begin clinical trials using new drugs in the acute phase of transverse myelitis and multiple sclerosis. Therefore, this research study will provide the fundamental groundwork to further our understanding of the pathogenesis of TM and MS and development of new therapies.

Clinical trials in neuroprotection and immunomodulation: Neuroprotection: Testing the neuroprotective effects of potential therapeutic agents that may include; erythropoietin, phosphodiesterase type IV inhibitors, immunophilin ligands, or ion channel blockers in Phase I/II clinical trials.

Immunomodulation: These clinical trials will involve the development of novel immunomodulatory therapies and testing through the development of monoclonal antibodies. We will also develop and test the immunomodulatory properties of Kv1.3 antagonists which may block critical myelin memory immune effector cells.

Equipment: Major equipment is critical for us to carry out this collaborative research. Major equipment purchases and upgrades are excluded from traditional grant applications. We will need cutting edge proteomics, imaging, spectroscopy and microscopy equipment in order to complete the projects listed above.

Educate Physicians throughout the World
Clinical Fellowships in Neurology and Neuroimmunology: Our goal is to establish a fellowship that focuses on clinical research in these disorders. The fellowship will include training in statistics, immunology, clinical trial design, scale development, data analysis and clinical evaluation. Through this fellowship, we hope to train physicians who will be leaders in clinical research of neuroimmunologic rare diseases.

Training Program components:
1. To define the competencies required for clinical research rare neuroimmunologic disorders.
2. To train clinician scientists with these competencies who will carry out safe, well-controlled clinical research in rare neuroimmunologic disorders.
3. To examine outcomes of the process of selection and training for clinical research in terms of career choice and subsequent research activities. The outcomes data will allow continuous improvements in both selection and education.
4. To provide a paradigm for model training programs for other specialties and institutions.

We expect to accomplish these specific goals by teaching methods of clinical research, appropriate use of statistics, principles of epidemiology, writing and presentation of biomedical data, research ethics, understanding conflict of interest, and quantitative methods for use in neurological research. All of this will culminate in an improved ability to define and conduct safe clinically applicable patient-oriented research.

Design and Methods
Our purpose is to provide three years of research training for physicians planning on a career in clinical research. We will offer a masters program with or without a thesis requirement in accordance with existing requirements for graduate programs at Johns Hopkins. Our proposed program will take full advantage of the current graduate training program in clinical investigation jointly sponsored by the School of Medicine and School of Hygiene and Public Health at Johns Hopkins. The program has been in existence since 1992. There will be a year of full-time academic classroom work followed by a year of mentored training in clinical or translational research in neuroimmunology. The current program can be audited without a degree, can lead to a master of science in clinical investigation, or can be expanded by one-to-two years to include a Ph.D. degree in clinical investigation. We expect that the primary pool of applicants will be neurology residents who are committed to an academic career in clinical research. Applicants from related disciplines, including immunology, anesthesia, intensive care, and neuroradiology, will be considered.

Educational symposia: Our goal is to educate physicians, patients and their families about MS, TM and other such rare neuroimmunologic disorders through interactions with scientists, clinicians and patient advocacy groups via international symposia to be held once every 2 years.

Electronic newsletters and maintenance of websites: Our goal is to inform patients, scientists and clinicians of our progress. To this effect e-newsletters will be sent every six months in addition to routine website updates.