Daniel Drachman MD

Professor of Neurology and Neuroscience

Telephone Number: 410-955-5406
Fax Number: 410-955-1961

Johns Hopkins Hospital
Department of Neurology
600 North Wolfe Street
Baltimore, MD 21205
Room: Meyer 5-119
Areas of Research
Cellular + Molecular Neuroscience
Neurobiology of Disease

Graduate Program Affiliations

Neuroscience Training Program

Rational Therapeutic Strategies for Treatment of Neuromuscular Diseases

Research in our laboratory focuses primarily on the design of rational therapeutic strategies for treatment of Neuromuscular diseases. Basic work in this laboratory coupled with clinical application has led to the development of many of the treatments currently used for myasthenia gravis (MG) and other autoimmune disorders of the neuromuscular system, as well as treatment of Duchenne muscular dystrophy with adrenal corticosteroids. At present our two main areas of interest are MG and amyotrophic lateral sclerosis (ALS, or "Lou Gehrig's disease). Myasthenia gravis: The basic abnormality in MG is a decrease of acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune response. We have elucidated the mechanisms by which the autoantibodies reduce the number of available AChRs and thereby produce weakness. We are developing a strategy to target and eliminate the T lymphocytes that are specific for the autoimmune response, and that provide "help" for production of the pathogenic autoantibodies in MG. This strategy utilizes gene transfer by viral vectors to modify the antigen presenting cells (dendritic cells) so that they target the autoreactive T cells, and instead of stimulating the T cells, they are armed with a "warhead" consisting of Fas ligand so as to induce apoptosis of the targeted lymphocytes. The advantages of this strategy are (1) That it is specific for the abnormal T cells, while leaving the remainder of the immune system intact; and (2) That it will be able to eliminate the entire heterogeneous repertoire of pathogenic T cells for that individual, and thereby remove all of these cells. This strategy will be applicable not only to the treatment of MG, but also of other autoimmune disease in which the autoantigen is known. ALS: This disease destroys motor neurons, leading inexorably to increasing weakness and death. Recent advances in understanding the pathogenesis of ALS have identified candidate therapeutic genes that have been shown to produce benefits in culture and animal models of ALS. Transfer of these genes to motor neurons may be effective for the treatment of ALS provided that they can be delivered efficiently to motor neurons. However, one of the most frustrating problems in devising treatments for motor neuron disorders is the difficulty of delivering therapeutic agents or related genes of interest to the motor neurons. Our approach makes use of the exquisitely specific ability of botulinum toxin to bind to and enter cholinergic motor neurons. We have cloned the (non-toxic) domain of botulinum that is responsible for this process, and have prepared fusion proteins that allow it to be used to transport viral vectors carrying potentially therapeutic genes of interest into motor neurons. We are working out methods of optimizing this strategy for the treatment of ALS and other motor neuron diseases.

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