ALS

Amyotrophic Lateral Sclerosis Disease (ALS)

What is ALS?
Background
Gene Discovery
Basic Science
Drug Discovery
Ideas for Potential Therapeutics
Human and Mouse Drug Trials
Resources

What is Amyotrophic Lateral Sclerosis? (source: NIH/NINDS)
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a rare illness that at any one time affects one in approximately 40,000 Americans, with 5,000 new diagnoses each year in the United States. ALS occurs when specific nerve cells in the brain and spinal cord that control voluntary movement— called motor neurons—gradually stop working correctly. Symptoms may include twitching and cramping of muscles, clumsiness and fatigue, or difficulty speaking or swallowing. Bladder and bowel function, sexual function and sight, hearing, smell, taste and touch are generally not affected. ALS usually strikes in mid-life and progresses at different rates in different patients. There is currently no cure for ALS, however, there are many new treatments being tested in people with ALS to try to stop the illness. There is one FDA-approved drug for ALS called Riluzole. Supportive treatments that address symptoms are very helpful and important to the care of people with ALS.

Background - ALS Research at MIND
The Massachusetts General Hospital has the country’s most comprehensive program for ALS research, spanning the full range from clinical care to basic science research. The program includes genetic research, molecular research, drug discovery, animal studies, and human clinical trials of potential new therapies. This research is complemented and coordinated with a large, multidisciplinary outpatient practice staffed with ALS specialists- physicians, nurses, and therapists.

MIND’s ALS research effort is spearheaded by Dr. Robert Brown, who has worked in the field for more than 20 years and directs the internationally renown Day Laboratory for Neuromuscular Research. This laboratory brings together a dedicated group of scientists and physicians who are working to reveal ALS disease mechanisms and to find therapies for this devastating disorder. This group also conducts research on other neuromuscular disorders including Muscular Dystrophy, Miyoshi myopathy, adrenoleukodystrophy, and hereditary sensory neuropathy type 1.

The Day Laboratory collaborates with research institutions around the world including Drs. Jonathan Glass (Emory University), Ammar Al-Chalabi (King’s College, London), Hiroshi Mitsumoto (Columbia University), Orla Hardiman (Baumont Hospital, Ireland), Elizabeth Fisher (University College of London) and Roger Pamphlett (University of Sydney, Australia) and others.

MIND’s ALS clinical research effort is led by Dr. Merit Cudkowicz, who has worked in the field for more than 13 years and directs the internationally renown MGH Neurology Clinical Trials Unit (NCTU) and Northeast ALS Consortium (NEALS). Under her leadership, MGH has led 7 clinical trials of new therapies in ALS. She is also leading studies to develop better diagnostics and biomarkers for ALS.

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Gene Discovery
The cause of the majority of ALS is still a mystery. However, 10% of people with ALS inherit the illness (“familial”). Studying these families where ALS is very common has been essential to making research breakthroughs. Dr. Brown discovered the first ALS gene, superoxide dismutase (SOD1) in 1993, which led to the creation of mouse model of ALS in 1994. By studying mice with ALS, scientists learn about the process of degeneration of motor nerves in the brain and spinal cord. When discoveries suggest new treatments, these mice are powerful models for testing drugs efficiently.

After the first ALS gene mutation (SOD 1) was found, Dr. Brown led and participated in teams that discovered four other gene defects that cause rare familial ALS, ALS2, Dynactin, VAPB and most recently, angiogenin (ANG). This mutation provides an important clue to the cause of ALS, since the protein which it encodes, angiogenin, is involved in blood vessel growth and can cause oxidative stress in brain and other cells. The Day laboratory has also found genes that cause hyperkalemic paralysis, a type of sensory nerve degenerative disease, and genes that result in a type of muscular dystrophy. Each gene discovery catalyzes an explosion in research, as scientists around the world study the gene’s role in nerve cell function.

Susceptibility Genes
Since the Human Genome Project was completed in 2003, a new frontier of genetics has been established – finding gene mutations that may increase a person’s susceptibility to developing a disease, or conversely, mutations which may protect a person from a disease such as ALS.

To pursue the genetic basis of susceptibility, Dr. Brown, working with John Landers, PhD, queried the entire human genome, looking for common variations in people with ALS, as compared to people who did not have ALS. This project has taken several years from inception to completion, because it involves comparing more than 2,000 patients with 2,000 controls. The results of that study have preliminarily shown that one gene can dramatically affect the duration of the disease in sporadic ALS cases, but does not determine who gets the disease. Gene hunters in the Day Laboratory continue to use the latest technology to reveal the human genome roles in ALS. These young scientists include Dr. Thomas Kwiatkowski, Dr. John Landers, and Dr. Anne-Marie Wills, the AAN/ALSA clinical scientist fellow.

Basic Science- finding clues about ALS
By studying the molecules and proteins that are modified in brain cells affected by ALS, researchers at MIND hope to identify the most logical targets for potential treatments. The Day Laboratory has been at the forefront of research that describes the molecular events preceding and during the destruction of motor neurons throughout the relentless progression of ALS.

One major area of study is to characterize the motor neuron cell death process that is triggered by the mutant SOD1 protein in ALS. Studies have shown that the protein activates a series of “suicide genes” that mistakenly tell the cell to stop functioning and die. While SOD1 is typically thought to be involved in inherited cases of ALS, Dr. Daryl Bosco in the Day Laboratory is examining its role in sporadic ALS. Dr. Bosco uses mass spectroscopy to study the abnormal folding and oxidation of SOD1 in humans and mice.

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Basic Science Leads to Ideas for Therapeutics and Drug Discovery

Targeted protein therapy
A major challenge in treating brain disorders is getting drugs and other treatments across the blood brain barrier that normally prevents proteins and toxins from entering the central nervous system. The Day Laboratory’s Dr. Jonathan Francis is a scientist with a longstanding interest in the use of special molecules that mimic natural agents and thereby “trick” the brain barrier into opening. The goal is to have these molecules help deliver growth factors to neurons, in order to stimulate motor neuron repair and recovery. Dr. Francis has developed novel approaches to modifying proteins so that they are effectively labeled to be targeted to these neurons, and has demonstrated that this may be a viable approach for ALS. If this technique can be refined and tested in patients with ALS, it could also be used for other brain diseases like cancer, Parkinson’s, and stroke.

Stem Cell Transplantation Studies
Stem cells may be beneficial for a disease like ALS is several ways. They may eventually allow replacement of lost neurons, thereby helping to restore functions. They may be helpful by forming new support cells that make existing neurons healthier. And, stem cells may be useful as vehicles for delivering drugs to the nervous system. The Day Laboratory has investigated the effectiveness of administering stem cells to mouse models of ALS and collaborates closely with other Harvard Stem Cell institutions.

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Drug Discovery
At MIND, discoveries in the laboratory have immediate implications for development of potential therapeutics. The Day Laboratory aggressively pursues any idea that emerges from their science to see if there are existing drugs that could modify the disease.

To find completely novel compounds, MIND houses a high-throughput drug screening laboratory that collaborates with the Day Laboratory on drug discovery projects, and allows researchers to test their ideas with compounds that may slow or halt disease progression. Dr. Alex Kazantzev is head of this drug development lab, and works closely with Michelle Maxwell of the Day Laboratory.

The first step is to develop a miniature model of the disease mechanism with which drug interactions can be measured – this is called assay development. Developing an assay which can be used to screen drugs is a laborious process that can take more than a year of effort. Different ALS assays have been developed in the Day Laboratory: one that measures a compound’s effects on the cell death triggered by mutant SOD1, and another that looks for compounds that reduce the production of the SOD1 gene.

Once an assay is developed and refined, the lab can test drugs to see which compounds rescue the neurons. These procedures previously were done by hand, but now robotic equipment available at MIND’s drug screening laboratory as well as other institutions allows it to be done methodically and quickly. Any “hits” from the screening then undergo further testing and refinement before they are tried on animals.

Through collaborations with the National Institutes of Health, Harvard Medical School, Johns Hopkins University, Thomas Jefferson University and other institutions, these assays from the Day Laboratory are now being used at MIND and many other institutions, to screen hundreds of thousands of compounds. Our hope is that through sharing and collaboration we will gain access to the one or two compounds out of a million that can eventually be developed into effective treatment for ALS.

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Mouse Trials
MIND houses an animal laboratory that allows researchers to test promising drugs in mouse models of ALS, looking for drugs that delay the onset of the disease or improve survival. The close collaboration with ALS clinicians at the Neurology Clinical Trials Unit allows us to quickly translate findings in ALS mouse studies into human trials.

Human Clinical Trials
The mission of the MGH Neurology Clinical Trials Unit (NCTU) is to rapidly bring new advances from the laboratory into testing in people with ALS and other neurodegenerative disorders. The NCTU is comprised of over 20 clinical researchers who are experienced in clinical trial design and conduct for ALS and other neurodegenerative disorders. The Neurology Clinical Trials Unit, co-directed by Merit Cudkowicz and Steve Greenberg, was created to take discoveries from the laboratory bench all the way to patients with ALS and other neurodegenerative disorders. The NCTU has over 10 years’ experience with conducting multi-center clinical trials in ALS, including studies of Celecoxib, Topiramate, Arimoclomol, Creatine, Coenzyme Q10, Sodium Pheylbutrate and Ceftriaxone. The NCTU is also leading a national collaborative effort to create an ALS Sample Repository to develop better biomarkers for ALS.

Drs. Cudkowicz and Brown co-founded the Northeast ALS Consortium (NEALS), an organization of ALS scientists and clinical researchers from over 70 academic institutions from all over the country, that was formed to quickly and efficiently launch multi-center therapy trials in ALS. Dr. Cudkowicz is the Co-Director of NEALS and the MGH NCTU acts as the Coordination, Data Management and Biostatistics Center for NEALS. Please click on http://www.alsconsortium.org/trials.html for more information about ongoing clinical trials in ALS.

Clinical trials are coordinated with the comprehensive patient care provided at the MGH Neuromuscular Clinic. The Clinic offers a multidisciplinary team approach to treating ALS and supporting patients and their families. It also provides second opinions and diagnostic testing to confirm an ALS diagnosis.

A few examples of this exciting work include:

Dr. Cudkowicz is the Principal Investigator of a new Phase IIB clinical trial of Arimoclomol in people with ALS. Arimoclomol is a new therapeutic agent that helps prevent protein aggregation. A study in 390 people with ALS will begin enrolling participants soon. The study details will be posted shortly on www.clinicaltrials.gov.

Dr. Cudkowicz is leading a National Institute of Health funded clinical trial of Ceftriaxone in people with ALS. Research in several laboratories has shown that Ceftriaxone protects motor neurons by increasing the production of an important protein that helps remove glutamate. The study is currently enrolling participants throughout the United States. The study details are posted at www.clinicaltrials.gov and the NEALS website.

Dr. Cudkowicz has received funding from the ALSA to conduct a Multi-center Study for the Validation of ALS Biomarkers. The study is anticipated to start in early spring 2008.600 volunteers, across 18 sites in the United States will participate. This study hopes to fully utilize the novel metabolomics technologies to identify markers in blood or cerebrospinal fluid that contribute to the pathogenesis of ALS. The development of ALS biomarkers would facilitate earlier treatment intervention, monitoring treatment efficacy, and hopefully lead to the identification of therapeutic targets that could be used in drug development.

The MGH investigator Leigh Hochberg also leads the BrainGate Pilot Clinical Study to evaluate a new technology which consists of an internal sensor that detects brain cell activity and external processors that convert these brain signals into a computer-mediated output under the person's own control. This study is evaluating the safety of such a device as well as the quality, type, and usefulness of neural output control that participants can achieve by using their thoughts. Ultimately it is hoped that this technology will allow an individual with motor neuron disease or other paralyzing disease to control a computer cursor by thought.

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Resources

NIH/NINDS:
http://www.ninds.nih.gov/
http://www.ninds.nih.gov/health_and_medical/pubs/als.htm

Day Laboratory for Neuromuscular Research at Massachusetts General Hospital

ALS Links:
http://www.alsa.org/
http://www.alslinks.com/
North East ALS Consortium:
http://www.alsconsortium.org/
Muscular Dystrophy Association:
http://www.mdausa.org/home

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