Progress and Challenges in the Fight Against ALS

Christine Bain, Ph.D. May 28, 2024

Charcot, Gehrig, Hawking: A Journey Through ALS

When you hear the names Charcot, Gehrig, and Hawking, what comes to mind? These names are all linked by a shared thread: Amyotrophic Lateral Sclerosis, or ALS.

ALS, also known as Charcot disease, is named after Jean-Martin Charcot, a neurologist from the Pitié-Salpêtrière Hospital, France. He was the first to use the term Amyotrophic Lateral Sclerosis in the late 19th century¹. In the United States, ALS is often referred to as Lou Gehrig’s disease, named after the famous Yankees baseball player who was diagnosed with the condition and tragically passed away at the age of 36.

Stephen Hawking, the renowned physicist celebrated for his groundbreaking work on black holes and quantum gravity, revolutionizing our understanding of the universe, is perhaps the most well-known individual to have lived with ALS for decades. Diagnosed at the age of 21, Hawking defied the odds and continued his scientific pursuits for decades, passing away at the age of 76.

These three figures, with thousands of individuals with this disease worldwide, represent the many aspects of ALS, from its clinical discovery to its human impact, and their stories continue to inspire and inform our understanding of this devastating condition.

Pathogenesis and Genetic Diversity of ALS

ALS is a fatal neuromuscular disorder that impacts motor neurons in the brain and spinal cord, leading to progressive muscular atrophy and paralysis. The disease ultimately results in respiratory failure, typically within 2-3 years of symptom onset². Stephen Hawking’s case is singular and an incredible example of the variability of the disease and its progression, as he lived with ALS for more than 50 years.

ALS is a heterogeneous disease, with patients exhibiting varying degrees of upper and lower motor neuron involvement and variable progression rates. While over 30 genes have been identified as being associated or increasing the risk of with ALS, contributing to its genetic diversity², one common hallmark of ALS pathology is linked to mutations in the TARDBP gene. This gene encodes TDP-43 (TAR DNA-binding protein 43), which, when mutated, mislocalizes from the nucleus and forms aggregates in the cytoplasm of motor neurons and glial cells³. The cytoplasmic aggregates of TDP-43 are thought to be toxic, potentially through mechanisms like sequestration of other RNA-binding proteins, impairment of protein degradation pathways, disruption of normal cellular processes, and its seeding properties⁴. While presenting in sporadic form for the majority of patients (90-95%), inherited forms of ALS occur. These familial cases are often linked to mutations in three key genes: SOD1 (Cu-Zn superoxide dismutase)⁵, FUS (Fused in Sarcoma)⁶, and C9orf72, the latter being the most common genetic subtype of ALS due to an intronic hexanucleotide GGGGCC expansion⁷.

Overall, the pathophysiology of ALS remains complex and partially understood, which may account for the absence of disease-specific diagnosis biomarkers and approved disease-modifying therapies.

Biomarkers in ALS

Different types of biomarkers have been described in ALS including electrophysiological biomarkers, like the neurophysiological index, imaging and clinical biomarkers but also fluid biomarkers, such as neurofilament light chain (Nf-L), TDP-43, inflammatory or oxidative stress markers, as well as microRNAs (e.g., miR-181), or repeat RNA sequences (e.g., G4C2 or G2C4)⁸.

High Nf-L levels in blood or CSF correlate with more severe disease and can predict the timing of symptom onset in asymptomatic individuals with known ALS-causing mutations. For instance, Nf-L levels rise 6-12 months before symptoms occur in SOD1 mutation carriers, 3.5 years in a C9orf72 repeat expansion carriers, and 2 years in FUS mutation carriers⁹. While TDP-43 is a primary pathological feature of ALS, its potential as a responsive biomarker in cerebrospinal fluid (CSF) or blood is limited due to its ubiquitous expression, the unclear pathological underpinnings of the TDP-43 levels in these biofluids and the absence of reagents specifically detecting disease-associated misfolded forms of TDP-43⁸. However, alternative methods such as the seed-amplification assay, initially developed for the prion protein, can be used for the detection of misfolded TDP-43¹⁰. A novel approach builds on the consequences of TDP-43 function anomalies, quantifying – in CSF and blood samples of ALS patients – TDP-43-dependent cryptic peptides, resulting from the loss of TDP-43 splicing repression¹¹.

Identifying biomarkers that indicate early disease onset is vital for initiating treatments before significant clinical symptoms occur, understanding the pharmacodynamics of drugs and, monitoring disease progression. Many clinical trials struggle with determining whether the therapeutic target was engaged as intended. In this context, over 50 clinical trials of disease-modifying therapies (DMTs) have failed, partly due to the absence of reliable biomarkers for identifying individuals who are likely to benefit from the drug.

Deserted Therapeutic Landscape for ALS

As of 2022, there were 53 active drug development programs in ALS, with 31 in clinical development and 22 in preclinical development². Among these candidate drugs, neuroinflammation is the most represented category in clinical development, while genetic approaches are prevalent at the preclinical stage.

Today, three drugs, primarily aim to manage or minimize symptoms, have been approved by FDA. These therapies target key biological pathways: i) Riluzole: the first FDA-approved treatment, addresses glutamate release and excitotoxicity, ii) Edaravone: a free radical scavenging drug that targets oxidative stress which plays a central role in ALS and iii) Tofersen: an antisense oligonucleotide that reduces the amount of SOD1 protein produced in cases of inherited SOD1 toxic gain-of-function mutations².

Despite the modest impact of these FDA-approved drugs in slowing functional decline and extending life, a cure for ALS remains elusive. Further improving our understanding of the disease’s pathophysiology and discovering biomarkers for early diagnosis and disease monitoring will be pivotal in developing therapies that can reverse the course of this devastating illness. All these efforts are supported through concerted advocacy efforts and awareness campaigns which are crucial to drive research funding.

Raising Awareness and Funds for ALS

Efforts to combat ALS rely heavily on the support of foundations, patient advocacy groups, and various fundraising initiatives. One of these, that took the world by storm in the summer of 2014, is the Ice Bucket Challenge, launched by 3 young men living with ALS. Participants would pour a bucket of ice water over their heads, challenge others to do the same, all while donating for an ALS association. This viral movement, now celebrating its 10^th anniversary, has significantly increased public awareness and raised millions of dollars for ALS research.

Among other initiatives, ARSLA , a non-profit French organization dedicated to raising awareness about ALS, providing support to ALS patients and their families, is an initiative aimed at bringing attention to ALS and raising funds for research and patient care. Les Invincibles, another French organization, founded by three individuals with ALS and dedicated to raising funds for ALS research and supporting those affected by the disease. Their efforts include organizing events, mobilizing a growing community of well-known and unknowns supporting their actions, and collaborating with researchers to accelerate the development of new therapies.

Why do these efforts matter? Fundraising and advocacy efforts are vital for advancing ALS research, developing new therapies, and improving patient care. Contributions from these initiatives provide the financial resources necessary for conducting groundbreaking research, supporting clinical trials, and ultimately finding a cure for ALS.

KCAS Bio’s contribution to innovative ALS therapies

Unmet needs in ALS revolve around developing treatments that will reverse the damage of the disease. This entails the identification of biomarkers for early diagnosis and guiding clinical development and patient care. These goals are at the heart of the AURALS project, funded by the French government and the Auvergne Rhône-Alpes region.

The AURALS project brings together the neurological care unit led by Dr. Emilien Bernard at the Hospices Civils of Lyon, Axoltis Pharma, and KCAS Bio. Axoltis Pharma is developing an innovative therapy targeting key pathways, including neuroprotection, synaptic transmission, and brain barrier regeneration. KCAS Bio will leverage its comprehensive technological platform and expertise in the neurological field, along with its know-how in method development, to evaluate innovative biomarkers that predict disease progression and treatment efficacy.

Last but not least, KCAS Bio Lyon will participate in the” Eclats de Juin” initiative in 2024. Join us in making a meaningful impact in the fight against ALS.

Reach out to KCAS Bio today to learn more about how we can leverage conventional flow cytometry to support your research needs.

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