ALS, also known as Amyotrophic Lateral Sclerosis or Lou Gehrig’s Disease, is a rare but debilitating neurodegenerative disease that affects the motor nerve cells in the brain and spinal cord. The motor nerve cells start to not function properly, no longer sending impulses to the muscles. This leads to increased muscle weakness in all autonomic muscle control. However, ALS does not affect parasympathetic muscle control - so anything that you can’t physically control like bowel or bladder function.
In the US, 5,000 new people are diagnosed with ALS every year. Most people who develop the disease are between the ages of 40 and 70, with 55 being the average age at diagnosis. Cases can occur for people in their 20’s and 30’s but this is extremely rare. About 90% of ALS cases occur sporadically, with no family history and early indication. Although the life expectancy of a person with ALS averages about two to five years from the time of diagnosis, the disease is variable. Many people can live with the disease for five years or longer. In fact, more than half of all people with ALS live more than three years after diagnosis. Once ALS is diagnosed, the disease will always progress to eventual loss of ability to walk, speak, swallow, and breathe. How fast and in what order this occurs is very individualized for every person.
Currently the ALS Association is funding and conducting groundbreaking research into the disease of ALS - specifically into drug development, as there is currently no cure for the disease. The ALS Association, and many other ALS research groups, are focusing into 13 research areas to investigate ALS further. Learn more about those research areas below.
Genetically, only 10% of ALS cases are considered “familial,” or inherited from a family member. The remaining 90% of cases are sporadic, meaning the cause of the disease is unknown. There are a large number of genes that have been identified to be involved in both sporadic and familial ALS. With ongoing research, scientists are realizing that the line between sporadic and familial ALS is not as distinct and simple as previously thought - it is likely that inherited genetics still plays a major role in the development of sporadic ALS. Most of the research goals in genetics is identifying which genes are linked to ALS. If scientists can find which genes in the genome are associated with causing the disease, then they can then create drugs to target these specific genes and hopefully find a cure for the disease. Currently, 60% of genes associated with familial ALS have been discovered. However only very few genes associated with sporadic ALS have been identified. A loss of function of the angiogenin protein due to mutation in the gene is thought to be linked to some cases of ALS. This gene, SOD1, was one of the first genes associated with ALS to be identified. 25 ALS genes have been identified since the discovery of SOD1 in 1993. With an increase in DNA sequencing technology and lower costs to carry out sequencing, gene discovery has exploded recently. Since the Ice Bucket Challenge in 2014, four new genes have been discovered - TBK1, TUBA4A, NEK1 and C21orf2.
2. Disease Mechanisms
ALS attacks motor neurons, a special type of nerve cell, in the brain and spinal cord. Upper motor neurons send nerve impulses from the brain to the spinal cord while lower motor neurons send nerve impulses from the spinal cord to the muscles throughout the body. The degeneration of motor neurons in ALS eventually leads to the death of those neurons and therefore the loss in ability of the brain to initiate and control muscle movement. This leads to the loss in all voluntary muscle control and eventually to total paralyzation. One of the biggest questions in ALS research is what actually causes the disease. The ALS Association and others are looking into the disease mechanisms of ALS, or the actual action in the body that causes the disease. There are five current disease mechanisms being studied.
The first is axon structure and dynamics. Transport of materials up and down the length of the motor neuron is an important cellular process and damage to this process may play into the progression of ALS. Active transport along the neurons brings newly made materials to nerve endings and nutrients back to the cell body. Motor neurons may be particularly vulnerable to any genetic defect that stops axon material transport.
The second disease mechanism being studied is apoptosis and necrosis, otherwise known as cell death. Apoptosis is a programmed and organized cell death. When the cell does not receive enough supplies or has lived out its life span, the cell will kill itself through apoptosis. This is a normal physiological response. On the other hand, necrosis is cell death due to infection or direct injury to the cell. Necrosis causes an explosion of cell contents followed by inflammation and an immune system response. Halting apoptosis when it is producing degenerative change in the nervous system is now a prime goal for researchers trying to design effective treatments for ALS as well as for other neurological disorders.
Thirdly, scientists are investigating the role of the mitochondria in ALS. The mitochondria is an organelle located in every cell in the human body and it plays a huge role - it produces ATP, a molecule that is “fuel” for almost every chemical reaction in the body. In the case of motor neurons, they span all the way from the spinal cord to the ends of the fingers and toes and so require tons of energy, or ATP. The mitochondria also controls the amount of cellular calcium ions, which is important because calcium ions are required for the process of muscle contraction and relaxation. Research is pointing to actions originating in the mitochondria being an important part in the progression of ALS. Changes in the mitochondria can be seen before any physical changes and the mitochondria show damage early in the ALS disease process. This is critical information as it can be a tell tale sign to know you have ALS before any physical symptoms actually show.
Glutamate is a type of neurotransmitter - a small molecule that is released between the synapses of nerve cells and either excites or inhibits transmission of nerve signals from one nerve cell to the next. Neurotransmitters, including glutamate, are quickly cleared from the synaptic gap to keep the “nerve message” brief. If it is not cleared fast enough, it can be toxic because it causes a prolonged excitation of the nerve cells. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. New evidence points to glutamate misaction as a factor in ALS.
The last disease mechanism being investigated is the immune response and inflammation. Inflammation is part of the immune system’s response to protect injured cells or invasion by foreign pathogens. Normally, it is a healing process. However, sometimes inflammation can be counterproductive - especially if the body can’t downregulate the immune response and the inflammation continues for much longer than it should have. When this happens, the inflammation can attack the body’s own tissues and cause damage, as is the case in autoimmune diseases like Crohn’s disease. New research suggests that inflammation in the motor neurons causes the death of motor neurons in ALS. Several places in the inflammatory events that appear to accompany ALS might be amenable to drug action that could help in the disease. Possible therapeutic targets of this strategy include the immune system messengers such as TNFα and other signal molecules involved in the cascade of inflammation.
Disease mechanisms help define what actually causes ALS. ALS is a heterogeneous disease, meaning that there are many diverse ways that disease can occur. It is very likely that more than one disease process is occurring in a person living with ALS. One person’s ALS might be caused by an overactive immune response leading to inflammation of the motor neurons while that might have absolutely no importance in another person’s progression of the disease. Finding multiple disease mechanisms and pathways to target with drugs will help benefit all sorts of people with ALS. Understanding the disease mechanism helps researchers know what to target. Once they establish a therapeutic target, the drug development process can begin to create drugs that either up regulate, down regulate or abolish the target, which all depends on the type of drug target.
3. Environmental Factors
Researchers are also looking for specific lifestyle factors that can contribute to the development of ALS. It is most likely that environmental factors are not sufficient to cause disease but work in conjunction with genetic susceptibility. Multiple environmental factors have been linked to ALS including BMAA, smoking, warfare, extensive exercise, pesticides, viruses and toxins (metals, solvents, radiation and electromagnetic fields). Environmental studies are being carried out to get a better understanding of incidence, prevalence, mortality rate and signs and symptoms of ALS, as well as the patterns of occurrence in relation to age, gender, race and geographic distribution. The association of ALS with environmental risk factors is being studied by comparing groups of people with ALS to groups of people who do not have ALS over time.
4. Disease Models
Disease models are other organisms used in lieu of humans for scientific research and help researchers understand the basic processes of the disease. No model is a perfect representation of the human disease, but each model offers advantages for studying some aspect of the disease.
5. Drug Development
The drug development process is long and costly - taking upwards of 5 years and $1-3 billion dollars before reaching FDA approval. A variety of treatment approaches are currently in development to treat ALS. Researchers first need to identify pathways relevant to the disease. From there, they can identify a small molecule or protein that will be the drug target. Chemical entities, usually small molecules, are screened to see if they can interact with the target of choice. From there, chemical alterations can be made to the small molecule in order for it to better interact with its target or to cross the blood brain barrier, which is critically important in a brain disease like ALS. From there, researchers see what other molecules in the body that small molecule interacts with and other side effects it may cause, as well as toxicity effects. Once a drug has been screened for all of these things, it can go into safety and efficacy clinical trials.
6. Clinical Studies
Clinical trials are used to determine whether a drug therapy is safe, counters the effects of the disease, and is also efficient (or more efficient than any other drug currently on the market) in humans. Before human trials, trials are done in cells grown in the lab and then in animals. There are two types of trials - observational and interventional. An observational trial is where patients are only observed and no treatment is given. These are often used to learn about trends of symptoms, the course of the disease, and to find disease biomarkers. Interventional trials are where patients are exposed to a drug. It is used to determine the effectiveness of a treatment or intervention.
There are three phases of human clinical trials. Phase I includes testing the safety of a drug treatment, often in twenty or less people. Participants are examined for any adverse reactions or side effects. If any appear that are judged to be too dangerous, testing is halted and the drug will not advance any further in the clinical trials process. Phase II attempts to determine the optimal dose and timing of doses for ideal treatment. Usually less than 100 patients are involved in Phase II. The therapeutic effect of the drug is determined in Phase III. This is the stage of testing that enrolls enough patients to allow a statistical judgment that a treatment is effective. Phase III requires hundreds to thousands of patients. Since ALS is so heterogeneous and disease progression is highly variable from one person to another, it requires even more patients in Phase III trials.
Biomarkers are any measurable substance that changes quantity with a change in the state of the body. In addition, structures in the body that change with a disease state could serve as a biomarker. Biomarkers that inform about disease progression should be sensitive enough to demonstrate changes during the disease process and are valuable tools to assess whether a drug is impacting the disease process of interest. Other ALS biomarker discoveries would be imaging techniques that can show changes in the brain or spinal cord specific to ALS. Together, any measure that changes with ALS and/or is specific for ALS, and will not confuse ALS with another disorder, could serve as a biomarker for the disease. Biomarkers are used to follow disease progression and track responses to drug therapies. They are important to see if a drug is actually hitting it’s therapeutic target and whether the drug is working or not. Biomarkers could also be used to detect ALS in early stages of the disease. Another goal of determining ALS biomarkers is to stratify patients into clinical trials. ALS is a complex heterogeneous disease with many diverse pathways. Stratifying patients with similar disease pathways allows the trial to have a more homogenous population where one drug would have a higher chance of being more effective. This will ensure that clinical trial outcomes are more informative and will encourage more participation from the industry sector.
The last few years have seen a great increase in advances in biomaterial science and nanotechnology. By definition, nanotechnology is the science of studying objects that are 1 to 100 nanometers in scale, such as molecules and atoms. The prefix “nano” means one billionth or 10-9, meaning one-billionth of a meter.
9. Precision Medicine
Precision medicine is the specific tailoring of treatment to each individual person. Researchers aim to learn as much as possible from each unique person living with ALS. iPSCs from people with ALS can be used in a variety of ways including serving as disease models, in drug screening, as a resource for biomarker development, and measuring drug efficacy in clinical trials. This precision medicine data can help stratify patients into more defined populations for clinical trials with the hope that smaller numbers of patients will be required to determine the effect of a treatment approach.
10. Cognitive Studies
It was recently thought that ALS did not cause any cognitive changes with disease progression. However, new research has linked ALS and FTD - frontotemporal dementia. ALS and FTD are now considered a spectrum disorder with pure ALS or pure FTD at either end of the spectrum and ALS combined with FTD to varying degrees. Most of the research in this area has been on the characterization of gene mutations that lead to both ALS and FTD. Research in FTD can give clues to ALS disease. Importantly, up to 40 percent of FTD cases carry a C9orf72 mutation, which is the most common genetic cause of ALS. More cognitive research studies will hopefully provide a target for drug development that will benefit both disorders.
11. Natural History Studies
The natural history of a disease is the course of the disease from initiation, through its various symptomatic stages until the final outcome without any treatment intervention. Natural history studies examine the course of the disease over time and give information about the disease. There are a few different types of natural history studies including retrospective studies, which look back and review records and medical histories, prospective studies, a study that examines clinical manifestations of affected individuals over time, and survey studies, where information is collected from people living with ALS, caregivers or others through questionnaires that are analyzed. ALS is considered a rare disease since it affects less than 200,000 people in the US. This means that the natural history of ALS is limited and natural history studies help fill in missing information. The goals of natural history studies are to support drug development and approval, help in clinical design trials, and aid in informing patient care as well as best practices and research priorities.
12. Assistive Technology
The last research focus area for ALS is assistive technology, or tools that help to improve the quality of life for patients already living with ALS. These include speech generating devices, eye gaze control systems (devices that use eye movement to select words to synthesize speech), brain computer interface (a system that allows a person to control a computer or other electronic devices using only his or her brainwaves with no movement required which can be used for communication or to control devices like wheelchairs), text to speech computer software programs, text to speech apps for phones, and voice banking systems (devices that allow people with ALS to store the sound of their voice and recorded words and phrases before they lose their ability to speak). Assistive technology is meant to help improve the lives of people with ALS by allowing them to become more independent, communicate their own medical decisions, and become a more active participant in their family and/or community. Caregivers and loved ones can also benefit from the advances in assistive technology by making their life easier and less stressful both physically and mentally.
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