What is ALS?

Amyotrophic lateral sclerosis, ALS, is a motor neuron disease characterized by degeneration of motor neurons in the brain, brainstem and spinal cord. This leads to progressive paralysis of the limbs, the diaphragm and the muscles of chewing, speaking and swallowing. Unfortunately, this progressive weakness leads to death, usually in about five years. Because ALS only affects motor neurons, it generally does not impair intelligence, memory, or sensory function.. There is no primary treatment for this disease although many symptomatic therapies are helpful.

There are two types of ALS: sporadic and familial. Sporadic ALS accounts for 90 of cases. Familial ALS (FALS) accounts for the remaining 10% of cases. Familial ALS is identified when more than one member of the same family develops the disease.

ALS shares at least two important basic properties with other brain-degenerative diseases, like Alzheimer's disease, Parkinson's disease and Huntington's disease. All are adult-onset disorders arising from neuronal death; all target specific subsets of neurons in the brain or spinal cord.

ALS Research Programs at the MGH

The Day Neuromuscular Research Laboratory and the Muscular Dystrophy Association sponsored clinic are internationally recognized for research and clinical care. Physicians and researchers have made many important contributions to the understanding of the biology of ALS. The following timeline highlights the ALS research breakthroughs and discoveries since the inception of the Day Neuromuscular Research Laboratory.

· 2001 - identification, with collaborators, of a gene defect causing juvenile ALS;
· 2001 - development of a rat model for ALS;
· 2001 - opening of the Center for Aging, Genetics, and Neurodegeneration;
· 1999 - beginning of stem cell research in ALS and related diseases;
· 1999 - identification of a gene address for ALS - dementia complex;
· 1997 - development of a Petri dish model for ALS;
· 1994 - identification of juvenile ALS gene address;
· 1993 - discovery of first ALS gene; this led to a mouse model of ALS in 1994
· 1991 - identification of adult ALS gene address;
· 1985 - initiation of the ALS genetics investigation;
· 1984 - inception of the Day Neuromuscular Research Laboratory MGH;
· 1980 - the first ALS research program at MGH and Harvard Medical School.

MGH Investigations of ALS Therapeutics

1. High Through-Put Drug Screening
An important approach to discovering drugs that may be beneficial in any disease is to develop miniature models of the disease. We have developed such models and are presently using them to screen libraries of drug compounds. Drugs that are beneficial in these assays will be tried in ALS mice and ultimately in ALS patients.

2. Stem Cell Therapy
This program explores the possibility stem cells have of replacing injured or dying tissues.

3. Gene Therapy
Our gene therapy program investigates the use of various vectors to deliver to the nervous system of ALS mice a variety of factors that improve nerve viability.

4. Allele Inactivation
An extremely powerful approach to treating the motor neuron cell death process in ALS is to shut down production of the offending or "killer" molecules. This arm of our program develops new methods to inactivate such neurotoxic genes.

5. Animal Models
Animal models of a disease like ALS are powerful because they provide a system for close analysis of the disease and for testing potential therapies. Accordingly, we will continue to invest a significant effort into the use of these animals to study ALS therapeutics.

6. Clinical Trials
The research initiatives above are laboratory-based. However, it is important that the program will be developed in a setting (MGH, Partners HealthCare System and Harvard Medical School) with a long-standing, strong tradition of clinical leadership in ALS. For example, through the auspices of the Neuromuscular Clinic and MDA Clinics at the Massachusetts General Hospital, we have an active service currently caring for 70-80 ALS patients. Clinical trials enable us to test the safety, dosage level and overall effectiveness of new drug therapies in patients. Our ALS clinical trials unit is presently conducting five clinical trials in ALS patients.

MGH Investigations of the Cause of ALS

1. Gene Expression Analysis
This approach tests the validity of current hypotheses about the cause of ALS and, in an unbiased manner, help to define new hypotheses. These, in turn, can provide insight into possible targets for drug treatment of this disease.

2. ALS Genetics
It is already evident in the research community that the analysis of genetic defects that cause ALS is a powerful approach to studying this disease. The underlying premise of these studies is that an understanding of genetic disturbances that trigger motor neuron death in families will illuminate aspects of ALS in all forms of ALS, particularly including the more common sporadic forms. In addition, this will also provide new insights that may lead to treatments.

3. ALS Biomarkers
Another approach to understanding the cell death process in human and mouse ALS is to acquire knowledge of l abnormalities that arise as the disease progresses. Tests to screen fluids and tissues of ALS patients for signature compounds that mark the presence of the ongoing disease process will be useful in defining underlying disease-causing mechanisms and in diagnosing the disease. Equally important, the ideal ALS biomarker will also assist in gauging the activity of the neuronal death process in ALS. Such a biomarker might be valuable in detecting beneficial effects of therapies more rapidly and sensitively than conventional analyses.