Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Goyal, Namita; Berry, James; Windebank, Anthony J.; Staff, Nathan P.; Maragakis, Nicholas J.; Berg, Leonard H. van den; Genge, Angela; Miller, Robert G.; Baloh, Robert H.; Kern, R.; Gothelf, Yaël; Lebovits, Chaim; Cudkowicz, Merit

doi:10.1002/mus.26801

Cited by 64 publications

(63 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, more precise readouts are highly sought-after. Hence, to efficiently target immunity in ALS, we need better diagnostic approaches for estimating inflammation, procedures to optimize duration and dosing for a desired therapeutic effect, and larger clinical trials with better patient stratification and appropriate controls ( Berry et al , 2017 ; Wosiski-Kuhn et al , 2019 a ; Goyal et al , 2020 ).…”

Section: Remaining Challenges For Translational Als Researchmentioning

confidence: 99%

“…Firstly, despite the well-known neurotoxic effects of inflammation, non-specific downregulation of the immune system limits neuroprotective and neuroreparative functions of CD4 T cells and microglia ( Schwartz and Shechter, 2010 ; Russo and McGavern, 2016 ). Secondly, ALS is a phenotypically and genetically heterogenous disease, so effective treatment necessitates stratified case monitoring ( Goyal et al , 2020 ). Finally, immunological biomarkers are necessary for precise tracking of immune responses from preclinical to the end disease stages, thus guiding precision medicine.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

View full text Add to dashboard Cite

Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

show abstract

Section: Remaining Challenges For Translational Als Researchmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

View full text Add to dashboard Cite

show abstract

“…ALS is a highly heterogeneous disease from a clinical and also from a genetic point of view [47]. This has implications for the efficient development of innovative therapeutics.…”

Section: Heterogeneity Of Als Patientsmentioning

confidence: 99%

“…This has implications for the efficient development of innovative therapeutics. For this reason, well defined inclusion or stratification criteria considering timing of the treatment and individual clinical features (e.g predictors of prognosis) might be considered with the aim of obtaining more homogeneous study cohorts [47,48].…”

Section: Heterogeneity Of Als Patientsmentioning

confidence: 99%

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Cappella

Pradat

Querin

et al. 2021

JND

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes on-going clinical trials in which antisense oligonucleotides are used in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

show abstract

“…Amyotrophic lateral sclerosis (ALS) has complex mechanisms and significant heterogeneity that has yet to be captured by an established biomarker. This may be an important reason for the failure of various clinical trials of candidate ALS therapies [1,2]. Therefore, it was necessary to develop a more sensitive disease outcome measure for ALS trials.…”

Section: Introductionmentioning

confidence: 99%

Chinese validation of the Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale

Sun

Fournier

et al. 2021

Euro J of Neurology

View full text Add to dashboard Cite

Background and purpose The Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) was developed using Rasch methodology. This scale has been demonstrated as a reliable outcome measure of amyotrophic lateral sclerosis (ALS) trials. To date, there are no similar interval‐weighted scales to assess disability in ALS patients. The current study aimed to validate a Chinese version of the ROADS via Rasch methodology. Methods The Chinese version of the ROADS was obtained through a standardized forward–backward translation and cultural adaptation. ALS patients were recruited from the Department of Neurology of Peking University Third Hospital in Beijing, China to complete the ROADS and the revised ALS Functional Rating Scale (ALSFRS‐R). Overall, 254 participants with ALS finished the Chinese scale. Rasch analysis was performed on the ROADS for validation and the ALSFRS‐R for comparison. Results The Chinese version of the ROADS was modified according to the statistical results. A final 28‐question scale was constructed that fulfilled all the requirements of the Rasch model with proper validity and reliability. Furthermore, the ROADS showed improved item targeting compared to the ALSFRS‐R. Conversely, the ALSFRS‐R did not fit the Rasch model expectations due to misfit values and disordered thresholds for all 12 items. Conclusions The Chinese adaptation of the ROADS is a linearly weighted scale that specifically captures overall disability in ALS patients. This scale indicates a wider range of item difficulties and better responsiveness than the ALSFRS‐R. The ROADS could be used as a valuable tool for use in ALS trials and in the clinic in Chinese settings.

show abstract

Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Cited by 64 publications

References 83 publications

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Chinese validation of the Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale

Contact Info

Product

Resources

About