Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig’s disease, is a progressive neurodegenerative disease that harms motor neurons in the brain and spinal cord, causing gradual muscle weakness, loss of movement, and paralysis . Approximately 30,000 people in the United States are affected by the disease annually, and 5,000 new cases are diagnosed every year . Researchers estimate that ALS causes close to 5 of every 100,000 deaths in people aged 20 or older . After diagnosis, about half ALS patients live three years or longer, 20% live five years or longer, and 10% live ten years or longer . With advances in research, namely stem cell therapy treatments, ALS patients may be able to live longer and more fulfilling lives.
ALS primarily attacks motor neurons, a type of neuronal cell that coordinates signals from the brain, spinal cord, and muscles to control voluntary and involuntary movement . Degeneration of motor neurons results in muscle weakness, gradual loss of movement, and eventual paralysis . In the early stages of the disease, ALS patients often experience muscle weakness, atrophy, and cramping.hey may trip and lose their balance when walking, slur their speech, have a weak grip, or struggle with other basic motor skills . Middle stages of ALS are marked by more widespread muscle weakness and some muscle paralysis, and patients might have trouble talking, swallowing, or breathing as muscles in the mouth, throat, and chest continue to weaken . In the final stages of ALS, the majority of voluntary muscles become paralyzed, and speech, eating, drinking, and breathing becomes difficult eventually leading to respiratory failure, the most common cause of death for people with ALS .
There are two forms of ALS: sporadic and familial . Sporadic ALS accounts for 90-95% of occurrences of ALS and has no clear cause. In contrast, familial or genetic ALS is inherited and responsible for 5-10% of cases of ALS. Children in families with genetic ALS are up to 50% likely to inherit a mutated gene and develop ALS . Over twelve genes have been attributed to ALS, including C9ORF72 and SOD1, where cases can be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant pattern .
ALS is difficult to diagnose, and as such, there is no single test or procedure to definitively diagnose the disease . Only through a series of tests, many of which aim at ruling out diseases that present similar symptoms to ALS, can a diagnosis be established . Electromyography (EMG), nerve conduction velocity (NCV), analysis of thyroid and parathyroid hormone levels and amount of heavy metals in blood and urine samples, spinal tap, x-rays and MRIs of the brain and spinal cord, myelogram (imaging of the spinal canal) of the cervical spine, muscle and nerve biopsies, and genetic testing if ALS runs in the family can all be used in diagnosis .
Currently, there is no cure for ALS, but various treatments can slow the loss of muscle strength and control, making patients more comfortable and self-sufficient . The United States Food and Drug Administration (FDA) approved drugs Rilutek (riluzole) and Radicava (edaravone) for treatment of the disease. Rilutek is being used in Canada, Australia, and some countries in Europe, while Radicava is also available in Canada, Japan, and South Korea . Rilutek has been found to interfere with glutamate activity and reduce glutamate toxicity, which has been linked to ALS severity . Radicava combats oxidative stress, an imbalance between reactive oxygen species (free radicals) and antioxidants, which is elevated in ALS cases [13, 16]. In edaravone Study 19 (MCI186-19), 137 patients were randomly given either Radicava or a placebo through intravenous infusions for a period of 24 weeks, and the ALSFRS-R scale was used to measure the progression of the disease . For the ALSFRS-R scale, patients rate their ability to complete a task on a five-point scale with 0 meaning unable to complete the task and 4 meaning normal ability, and the scores for each task are totaled with 0 being the worst and 48 being the best . After the six months, patients who received the placebo experienced an average loss of 7.5 points on the ALSFRS-R scale and those who were given Radicava experienced an average loss of only 5 points, making a strong case that Radicava slows deterioration in ALS patients compared to the placebo .
Stem Cell Therapy
Stem cell therapy is the future of treatment for ALS and countless other chronic diseases. Stem cells have the potential to cure life-threatening food allergies, repair damaged hearts, reverse neurodegeneration, and create chimeric human-animal organs for autologous organ transplantation. Current ALS treatments address symptoms like muscle pain, insomnia, and fatigue, and phenomena like oxidative stress and glutamate toxicity, but they do not tackle the heart of the issue: degeneration of motor neurons. Stem cells can wholly regenerate the motor neurons killed off in ALS, and Neurotrophic Growth Factors (NTFs) have been shown to extend the longevity of motor neurons . In a clinical trial by the Hadassah-Hebrew University Medical Organisation in Israel, mesenchymal stem cells (MSCs) were isolated from a patients’ bone marrow, expanded ex vivo, and induced to differentiate into MSC-NTF cells, using a medium with 1 mM of dibutyryl cyclic adenosine monophosphate, 20 ng/mL of human basic fibroblast growth factor, 5 ng/mL of human platelet-derived growth factor, and 50 ng/mL of human heregulin β1 .
In the first part (phase 1/2) of the trial, the MSC-NTF cells were administered by intramuscular (IM) injections at 24 separate sites to the biceps and triceps (1 × 106 cells/site) or by intrathecal (IT) administration of 1 × 106 kg/cells . In the second stage (phase 2a) of the study, the patients were treated with both IT and IM injections in 3 dosing cohorts (low dose: 1 × 106 cells/kg IT and 24 × 106 cells IM; mid-dose: 1.5 × 106 cells/kg IT and 36 × 106 cells IM; and high dose: 2 × 106 cells/kg IT and 48 × 106 cells IM) .
Lymphocyte markers on blood mononuclear cells, muscle volume measured through MRI scans of the arm, and compound muscle action potentials (CMAPs) of the bicep muscle were analyzed . The treatment was safe and well-tolerated by patients. They experienced a slower rate of disease progression from 6 months after the transplantation to 3 months after . Rate of disease progression was determined by the ALS Functional Rating Scale in which patients rate their ability to perform tasks on a 5-point scale (ranging from 0 = unable to complete the task to 4 = normal ability) and Forced Vital Capacity (FVC), which measures lung function .
In another study, primary skin cells were isolated by biopsy from an 82-year-old woman with familial ALS, the rarer form of the disease . KLF4, SOX2, OCT4, and c-MYC transcription factors were introduced into these cells by virus vesicular stomatitis glycoprotein (VSVg) to create induced pluripotent stem cells (iPSCs) .
The three iPCS cell lines from the patient formed embryoid bodies and differentiated spontaneously into cell types representative of the three germ layers, indicating pluripotency . The iPCS were able to be differentiated into motor neurons, which are destroyed in patients with ALS, and is unique from any other ALS treatment .
There is also a growing body of research into the role of astrocytes, glial cells in the central nervous system, in ALS. Instead of dying like motor neurons, astrocytes become dysfunctional and create a toxic environment that harms the motor neurons they conventionally support . Dr. Clive Svendensen recognized the challenges that come with trying to replace motor neurons in adults and instead turned towards a strategy of replacing damaged astrocytes with healthy ones . He aimed to generate healthy astrocytes from brain stem cells that produce glial cell line-derived neurotrophic factor (GDNF), a protein essential to motor neuron health, and then transplant these cells into the patient’s spinal cord [22, 23]. Cedars-Sinai Medical Center received approval from the FDA to test the treatment on 18 ALS patients and began the trial in May of 2017 .
Biotechnology company CORESTEM’s product NeuroNata-R, the world’s first stem cell-based therapy for ALS, was approved by the Ministry of Food and Drug Safety (MFDS) in South Korea in July of 2014 and was launched commercially in February 2015 . Treatment involves extracting bone marrow from the patient, isolating and culturing mesenchymal stem cells from the bone marrow, mixing MSCs and cerebrospinal fluid from patients, and injecting the treatment intrathecally . CORESTEM is looking to expand NeuroNata-R’s use to the United States and Europe, and as of March of 2019, 371 patients with ALS have safely received NeuroNata-R in South Korea, 256 of those patients since the commercialization of the treatment . Data from clinical trials have shown NeuroNata-R to slow the progression of the disease as measured by the ALSFRS-R scores of patients before and after treatment and compared to a control group .
Current treatments for ALS primarily aim to alleviate symptoms like fatigue or slow down progressive muscle loss and weakness, but they can only go so far as they do not address the true problem: degeneration of motor neurons. In recent years, there has been a growing body of research into using stem-cell-based approaches like adding neurotrophic growth factors, differentiating iPSCs into motor neurons, generating health astrocytes from brain stem cells, and injecting MSCs mixed with cerebrospinal fluid into the spinal canal. Stem cell therapy has been clinically shown to slow the progression of the disease. With further research, stem cell therapy could yield an eventual cure for ALS, and it will undoubtedly shape the future of medicine.
Hello! My name is Natasha Matta, and I'm a high school junior from the San Francisco Bay Area interested in cognitive neuroscience, psychopathology, neurodegenerative diseases, and neurolaw. My research focuses on a novel network approach to diagnosing and understanding the highly misunderstood adolescent borderline personality disorder and mapping its connections to ADHD and ODD in childhood for patient-specific treatment and opportunities for early intervention.