Amyotrophic Lateral Sclerosis (ALS)
If you have reached this web site you likely know more than you wish about amyotrophic lateral sclerosis, commonly referred to as ALS , that most of us have heard about at one time or other but don’t think much about until we are personally affected. And while the name is reasonably descriptive to the medically informed, to the average person it does not mean much and the same can be said for the other terms that are used interchangeably for ALS: motor neuron disease and Lou Gehrig’s disease. As in the instance of other degenerative conditions of the nervous system, such as Alzheimer’s and Huntington’s disease, progress in understanding ALS was slow from the middle of the 19th century when the disease was first described to about the middle of the 20th century when the pace of research picked up.
Looking back two factors can be seen as turning points. Following WWII, American neurologists drew attention to the occurrence of ALS in Guam where the incidence of the disease was markedly elevated compared to the rest of the world and scientists demonstrated that some neurodegenerative diseases were either due to common viruses such as measles or to infectious agents, now known as prions, that were unlike anything that had ever been known before. From time to time it looked like these advances were going to shed light on the riddle of ALS but more recent developments have thus far been more fruitful. Chief among these has been the discovery of genes that cause ALS. The first of these, mutations of a gene that codes for a protein that stabilizes free radicals (superoxide dismutase), was discovered in 1993. Not long after the abnormal human gene was inserted into mice and then rats, both of which come down with ALS. Even though familial forms of ALS represent a minority of the total number of cases, the availability of an ALS animal model has provided researchers with a tool to study the disease process and spear head the development of treatments for the disease. And going a step further a “test tube” model of ALS has been made possible by generating stem cells derived from skin biopsies taken from patients.
Whatever the cause of ALS, the brunt of the disease process is borne by the spinal cord and lower part of the brain, leading to paralysis and spasticity. Normally, nerve cells occupy most of the ventral horn of the spine cord (see figure 1) but as ALS progresses there is a marked loss of nerve cells in the spinal cord and brainstem. Inexplicably the degenerative process is not wide spread. If it was many other neurological functions would be lost but the process is more extensive than once thought. The more doctors have looked, the more they have appreciated the full extent of the disease process. For example, some patients exhibit experience difficulty with communication. And using advanced imaging techniques such as PET scanning, abnormalities can be seen in the brain. Working with colleagues at Scripps we have recently recorded abnormal magnetic signals emanating from the brains of ALS patients using a technique called magnetoelectoencephalography (Fig 2). These abnormalities were seen in patients who had only recently been diagnosed, suggesting that much of the central nervous system is involved from the onset. Based on these finding we consider it likely that the disease starts in the brain and going further we have concluded that the brain drives the disease process. This may be a leap but it may be possible to design an animal experiment that supports this conception.
Since Congress declared the 1990s to be the decade of the brain we have learned more about the nervous system than had been known over all of human history. But in spite of this we still don’t know what causes sporadic ALS which accounts for better than 90% of cases. And even in the instance of familial ALS it is still not known how a mutation of a gene such as SOD causes nerve cells to degenerate. But there are a lot of clues as to how this occurs. For example, motor neurons have been noted to accumulate a number of proteins which, under a microscope, can be seen as inclusions (Fig 3). Intuitively one would think that inclusions damage and possibly kill nerve cells but even this is not certain. In fact, just the opposite may be true. Inclusions may be sequestering abnormal proteins in an effort to neutralize their toxicity. Currently several therapeutic approaches are being implemented based on the belief that the production or disposal of proteins is central to the pathogenesis of ALS. The first of these approaches involves the experimental treatment of patients with a drug (Arimicol) that up regulates the expression of heat shock proteins (fig 4). These facilitate the folding of proteins and the clearance of damaged ones. Using an animal model of ALS a very modest increase in life span is noted in treated animals treated with Arimicol compared to controls (fig 5). Based on these results a clinical trial is underway to test the usefulness of this therapy.
Our own research has taken a different treatment approach in ALS patients with a mutation of SOD. Since patients remain well for years before they develop ALS, in spite of the fact that the mutated protein is present from birth, we reasoned we could restore patients to good health by reducing the amount of SOD that is produced. This assumes that patients ultimately become ill when the equilibrium between the production of the mutant protein and its disposal is out of balance. By reducing the amount of the mutant protein, which we infer is toxic to cells when it can not be purged, we are betting that the body will literally heal itself. To investigate this possibility we have collaborated with Isis Pharmaceutical Corporation in Carlsbad, California and with Don Cleveland, Ph.D. at the Ludwig Institute which is part of the University of California, San Diego. At the outset we designed and screened a panel of DNA molecules (ASOs) to find ones that targeted the expression of SOD in a cell culture system (fig 6, fig 6a). These molecules work by interfering with the molecular machinery that produces proteins. And importantly the treatment effect is specific; otherwise, it would be deleterious since interfering with the production of all proteins would have serious consequences. Since many molecules do not readily reach the brain after administration we elected to inject them directly into the spinal fluid which bathes the brain. To our delight this mode of delivery proved to be very effective since both neurons and non neuronal cells avidly take up the molecules (fig 7). Even more critical is the finding that the ASOs were just as effective in jamming the molecular machinery responsible for protein synthesis in an animal as they were in cells grown in a Petri dish (fig 8, fig 8a, fig 8b, fig 8c). And when we were able to show that we could markedly prolong survival in rats destined to develop ALS we were optimistic that this therapy could work in patients with familial ALS (fig 9, fig 9a, fig 9b). A human trial, supported by the Muscular Dystrophy Association and the ALS association, is planned for this year if approved by FDA. The nationwide trial will be undertaken in collaboration with Washington University (Dr Timothy Miller), Harvard (Merit Cudkowicz), John Hopkins (Jeff Rothstein) & Methodist Hospital (Stan Appel) and ourselves at Scripps (Isaac Bakst).
Another fascinating twist to the ALS story occurred several years ago when a cancer researcher discovered a connection between ALS and a hormone (VEGF) that controls the growth of blood vessels. Dr Carmeliet who works in Belgium wanted to develop mice that did not produce VEGF. If these animals did not develop tumors after being injected with malignant cells he presumed that a drug that exhibited similar properties would be a useful treatment for some cancers. To his surprise animals that could not make VEGF developed ALS. And with further study it was found that persons who carry a mutation of the VEGF gene are at increased risk for ALS. And as you might expect, researchers soon speculated that VEGF could be a treatment for ALS as it proved to be in the animal model (fig 10). At CCR we are testing this idea along with 5 other centers using a unique treatment strategy. Instead of administering VEGF to patients researchers at CCR are injecting a DNA molecule that instructs the body to make VEGF into the muscles of ALS patients. The molecule, called a plasmid, is a small circular piece of DNA. It was designed by Sangamo Biosciences which is a Biotech company located in northern California.
As it turns out a role for hormones in the genesis of neurodegenerative disease can be traced back to the 1940s with the discovery of nerve growth factor. Early in development neurotrophic factors determine the number of neurons that populate the brain and they provide trophic support. Realizing that it might be possible to slow or arrest ALS with the administration a hormone, researchers including Dr Richard Smith who is associated with CCR conducted the first treatment experiment to test this idea in ALS. In the late 1980s they undertook a controlled study to determine if Protropin, synthetic growth hormone, exerted a favorable effect on ALS. The idea was to boost levels of another hormone called IGF-1 which is known to work in the brain. This study, undertaken with Genentech corporation and supported by MDA was the most exhaustive treatment trial ever taken in ALS. Patients were closely monitored and each month blood levels of IGF-1 were recorded to be sure patients were taking the drug and to be certain that the drug was having the desired biologic effect. Further, muscle strength was carefully monitored using an elaborate device as was respiratory function. Unfortunately the treatment had no effect. However, an argument can be made that treatment might work if one could get the drug to the brain. But instead of trying to do this it was decided to repeat the same experiment over and over again at an unimaginable cost with the latest result ending up, more or less, as we first reported it (fig 11). And the matter would probably have died were it not for the work of Brian Kaspar and Fred Gage at the Salk Institute who figured out an improved means of delivering IGF-1 to the brain: instruct the brain to make more hormone using a gene therapy approach. They packaged the needed genetic instructions into a virus which they injected into the muscles of mice destined to get ALS (fig 12). The virus was carried along nerves into the nervous system which began to produce IGF-1. Remarkably, treated animals experienced a striking increase in their survival, suggesting that a similar treatment strategy might work in humans. A company in San Diego is attempting to conduct such a trial but the methodology employed in the animal experiment needs to be further refined. And for the moment we have no opinion as to the use of IPLEX which a European company manufactures and endorses as a means of treating ALS with yet another version of IGF-1.
Another treatment idea that has been around for sometime deserves comment, namely the notion that the regulation of glutamate and/or aspartate is causally connected to ALS.
This idea dates to the 1960s when John Olney, a scientist at Washington University, discovered that drugs that blocked the glutamate receptor could be neuroprotective (fig 13). Until then it was believed that nerve cells could not survive if they were stressed for too long, in his experiments by interrupting the blood supply to the brain. On this basis Riluzole, the only approved drug for ALS, was discovered and ultimately shown to exert a modest effect on survival in treated patients. About the same time Dennis Choi and his colleagues at Stanford discovered that dextromethorphan, a medication commonly used as a cough suppressant, blocked glutamate. But administration of this medication was unreliable because the drug is rapidly degraded by most of the population. To get around this obstacle we developed a novel formulation of DM and initiated studies in a small group of ALS patients. To our surprise we discovered that DM exerted a number of palliative effects in ALS patients and some other disorders. Principle among these was an effect on emotional lability that occurs in approximately 30% of ALS patients (fig. 14). Currently, Avanir pharmaceutical corporation is testing this again in a second, large clinical study, with the expectation that the results will be known later in the year. And we are confident that further study will document other beneficial effects for this drug. CCR is privileged to be one of the clinical sites for this study which is ongoing although enrollment is now closed.
While no plans, to our knowledge, are in place to determine if our DM formulation will modify the course of ALS the “excitotoxicity hypothesis” is undergoing several other tests. One of these is based on seminal observations made by Jeffrey Rothstein and his colleagues at John Hopkins. They observed that the glutamate transporter which is involved in recycling glutamate after it has been released at the synapse is impacted in the ALS animal model (fig 15). Subsequently they screened a extensive group of drugs to determine if any could up regulate the synthesis of the transporter. This revealed that Ceftriaxone, an antibiotic, had such an effect (fig 16). Currently, a nationwide trial is underway to test the effectiveness of this treatment strategy. And based on a similar rationale a drug that blocks the kainate receptor is also being tested in a clinical trial by TEVA pharmaceutical corporation.
While this site is not intended to provide a thorough review of ALS it is hoped that we will keep you, the reader, apprised of new developments that are likely to impact the development of new and better therapies. And it should be obvious from this brief outline that the pace and depth of ALS research has increased exponentially over the last few years, leading to the realistic expectation that meaningful advances in our understanding of the disease and its treatment are imminent.