Unraveling Amyotrophic Lateral Sclerosis (ALS): Mechanisms, Pharmacology, and Advances in Treatment
Location
Suwanee, GA
Start Date
6-5-2025 1:00 PM
End Date
6-5-2025 4:00 PM
Description
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease that selectively affects motor neurons, leading to muscle weakness, paralysis, and respiratory failure. With an incidence of 2–3 per 100,000 annually, ALS primarily presents in middle age and follows a rapidly progressive course, resulting in a 2–5 year median survival post-diagnosis. While 90% of cases are sporadic, 10% are familial, often linked to mutations in SOD1, C9ORF72, TARDBP, and FUS, which disrupt key neuronal processes such as glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, and protein misfolding. These mechanisms contribute to motor neuron degeneration and form the basis for emerging targeted therapies. The diagnosis of ALS remains clinical, requiring evidence of both upper and lower motor neuron involvement. Upper motor neuron signs include spasticity, hyperreflexia, and Babinski’s sign, while lower motor neuron signs manifest as muscle atrophy, fasciculations, and weakness. Electromyography (EMG) and nerve conduction studies (NCS) are critical for detecting motor neuron loss, and newer imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) hold promise for early diagnosis and monitoring. Despite advancements in understanding ALS pathophysiology, Riluzole (a glutamate modulator) and Edaravone (an antioxidant) remain the only FDA-approved treatments, offering limited survival benefits. However, emerging therapies such as gene editing (CRISPR-based approaches), antisense oligonucleotides (Tofersen for SOD1 mutations), and novel neuroprotective agents (AMX0035, targeting mitochondrial and endoplasmic reticulum stress) are currently being explored. Additionally, biomarkers like neurofilament light chain (NfL) in plasma and cerebrospinal fluid (CSF) are improving early detection and patient stratification in clinical trials. The economic and clinical burden of ALS remains high due to its rapid progression, lack of curative treatments, and need for multidisciplinary care, including respiratory and nutritional support. Future research must focus on identifying novel drug targets, optimizing biomarker use, and integrating precision medicine approaches to improve patient outcomes. Interdisciplinary collaboration in genetics, neuroscience, and clinical research is crucial to accelerating therapeutic discovery and, ultimately, finding a cure for this devastating disease.
Embargo Period
5-19-2025
Unraveling Amyotrophic Lateral Sclerosis (ALS): Mechanisms, Pharmacology, and Advances in Treatment
Suwanee, GA
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease that selectively affects motor neurons, leading to muscle weakness, paralysis, and respiratory failure. With an incidence of 2–3 per 100,000 annually, ALS primarily presents in middle age and follows a rapidly progressive course, resulting in a 2–5 year median survival post-diagnosis. While 90% of cases are sporadic, 10% are familial, often linked to mutations in SOD1, C9ORF72, TARDBP, and FUS, which disrupt key neuronal processes such as glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, and protein misfolding. These mechanisms contribute to motor neuron degeneration and form the basis for emerging targeted therapies. The diagnosis of ALS remains clinical, requiring evidence of both upper and lower motor neuron involvement. Upper motor neuron signs include spasticity, hyperreflexia, and Babinski’s sign, while lower motor neuron signs manifest as muscle atrophy, fasciculations, and weakness. Electromyography (EMG) and nerve conduction studies (NCS) are critical for detecting motor neuron loss, and newer imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) hold promise for early diagnosis and monitoring. Despite advancements in understanding ALS pathophysiology, Riluzole (a glutamate modulator) and Edaravone (an antioxidant) remain the only FDA-approved treatments, offering limited survival benefits. However, emerging therapies such as gene editing (CRISPR-based approaches), antisense oligonucleotides (Tofersen for SOD1 mutations), and novel neuroprotective agents (AMX0035, targeting mitochondrial and endoplasmic reticulum stress) are currently being explored. Additionally, biomarkers like neurofilament light chain (NfL) in plasma and cerebrospinal fluid (CSF) are improving early detection and patient stratification in clinical trials. The economic and clinical burden of ALS remains high due to its rapid progression, lack of curative treatments, and need for multidisciplinary care, including respiratory and nutritional support. Future research must focus on identifying novel drug targets, optimizing biomarker use, and integrating precision medicine approaches to improve patient outcomes. Interdisciplinary collaboration in genetics, neuroscience, and clinical research is crucial to accelerating therapeutic discovery and, ultimately, finding a cure for this devastating disease.