Research Organization
The Packard Center's research staff belong to one or more of five teams, with each team following a different avenue:

1. Basic Mechanisms of Disease
   Scientists in this group study the molecular and cellular processes that cause ALS and related motor neuron diseases. Their basic work has had a major influence on current thinking about how motor neuron disorders originate.
   
   
2. Models of Human Disease
   The scientists in this group are committed to create and analyze models of ALS using laboratory cultures of cells, cultures of living spinal cord and living animals.
   Mice bred to carry defective human genes, for example, so-called transgenic mice, make especially useful models of disease. Mice with an abnormal human gene for a protective enzyme called superoxide dismutase (SOD1) develop ALS. These mutant mice become progressively weaker, with muscle atrophy virtually identical to that in the human disease. Transgenic mice not only help explain the nature of the disease, but, because they can be used to test therapies, they also become an invaluable step on the road to human trials.
   
   
3. Experimental Therapy
   Using models, Center scientists routinely test new therapies, hoping they'll halt or slow the decline of motor neurons. Typically, most test therapies are agents believed to have a neuroprotective effect. The success of several drugs such as riluzole, now used to slow ALS, began with model systems which include:
   o Transgenic rodent models
   o Models created by direct nerve cell injury or insult. These may involve tissues in which axons of motor nerve cells have been injured or tissues with damaged nerve cell bodies.
   o Models in which motor nerve cells are temporarily deprived of trophic factors-hormone like molecules produced elsewhere that nurture or attract the nerve cells.
   o Animal models of lower motor neuron disease (brought about by Sindbis virus)
   o Tissue culture models in which nerve cells have been overexcited and damaged by the neurotransmitter glutamate or in which nerve cells suffer oxidative injury.
   
   
4. Clinical Investigations
   The Center's clinicians follow large numbers of ALS patients throughout the course of their disease. Getting a feel for the diversity of the disease helps uncover new diagnostic methods. It also reveals new, atypical forms of ALS.

   Recently, for example, investigators used patient studies to identify a gene on human chromosome 9, responsible for a new variety of familial ALS marked by very slow progression. Further study will trace the gene's effects on nerve cells transfected with the gene. Center scientists will also observe its effects in transgenic mouse models.

5. Clinical Trials and the ALS Clinic
   Researcher-clinicians at the Packard Center for ALS Research are committed to move therapies from bench to bedside in rapid time while still insuring safety. Studies that show promise in the laboratory models are adapted for local, national or international clinical trials on human volunteers.

   Several years ago, for example, Packard Center Medical Director Jeffrey D.Rothstein, engaged in the earliest studies of a new class of drugs called glutamate antagonists, with a potential of slowing the disease. One specific drug, Riluzole, went through clinical trials at Hopkins and elsewhere. It's now available to patients, prolonging their survival. Currently, more potent drugs are in the ALS pipeline, undergoing testing in cell, tissue, organ and animal models. Trials of creatine, a natural chemical in the body's energy pathways, anti-inflammatory agents such as COX2 inhibitors and several types of stem cell are in the planning stages.

The clinical centers at Johns Hopkins Hospital and at the Bayview Medical Center have participated in more than a dozen national and international trials of therapies for neurodegenerative diseases, including Alzheimer's and ALS. Patients with ALS frequently sign up for trials within several months of diagnosis.

The Packard Center's studies have a reputation for excellence, largely because of their solid scientific basis and careful design. But the reputation also stems in part from the easy availability of Hopkins' long-established institutional "machinery" for such trials. Finally, the Center relies upon the expertise of Lora Clawson, manager of the Johns Hopkins ALS Clinic to coordinate patient participation in studies. Clawson oversees their pre- and post- trial exams, monitors and evaluates side effects and explains the studies to volunteer subjects. She protects the integrity of the trials, seeing that carefully-developed protocols are carried out.

The ALS Clinic
The ALS Clinic at Johns Hopkins Hospital provides multidisciplinary support for all ALS patients. This includes pulmonary assistance, speech therapy, tactics for improved swallowing and nutrition, physical therapy and support group meetings. The Clinic has been a central means to recruit patients for clinical trials. It also supports the donation, through autopsy, of tissues for research.

Core Support for Researchers
Pre-Clinical Therapeutic Models Available
The Center makes its several model systems available to members and collaborators worldwide, to study therapeutic possibilities of novel drugs, engineered cells and introduced genes.

Core Facility Offers Cells, Proteins
The Center also maintains cultures of cells, such as mutant SOD1 cells, as well as antibodies to SOD1, glutamate transporters, Copper Chaperone for SOD1 and new antibody reagents for researchers' use.