In recent clinical trials of pharmacological treatments, differential benefits have been noted in specific patient subgroups, often with more favourable results in patients with fast progressing ...amyotrophic lateral sclerosis. ...awareness of disease heterogeneity is increasing. ...there is a growing need to test novel pharmacological and genetic treatment approaches over a shorter trial period. A study by Maor-Nof and colleagues10 elucidated how the dipeptide protein poly-proline-arginine, which is generated from the repeat expansion, induces apoptotic pathways and, ultimately, neurodegeneration by epigenetic modulation of gene transcription via the transcription factor TP53, thereby indicating nucleoporin p54 ablation as a novel therapeutic strategy.10 Overall, amyotrophic lateral sclerosis research in 2021 has resulted in increasing knowledge on risk factors and mechanisms, and in advances in biomarker research and trial design.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both ...juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls. Patient-derived MNs show typical cytoplasmic FUS pathology, hypoexcitability, as well as progressive axonal transport defects. Axonal transport defects are rescued by CRISPR/Cas9-mediated genetic correction of the FUS mutation in patient-derived iPSCs. Moreover, these defects are reproduced by expressing mutant FUS in human embryonic stem cells (hESCs), whereas knockdown of endogenous FUS has no effect, confirming that these pathological changes are mutant FUS dependent. Pharmacological inhibition as well as genetic silencing of histone deacetylase 6 (HDAC6) increase α-tubulin acetylation, endoplasmic reticulum (ER)-mitochondrial overlay, and restore the axonal transport defects in patient-derived MNs.Amyotrophic lateral sclerosis (ALS) leads to selective loss of motor neurons. Using motor neurons derived from induced pluripotent stem cells from patients with ALS and FUS mutations, the authors demonstrate that axonal transport deficits that are observed in these cells can be rescued by HDAC6 inhibition.
Objective
Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high‐caloric diet increases survival. ...Therefore, we sought to evaluate the efficacy of a high‐caloric fatty diet (HCFD) for increasing survival.
Methods
A 1:1 randomized, placebo‐controlled, parallel‐group, double‐blinded trial (LIPCAL‐ALS study) was conducted between February 2015 and September 2018. Patients were followed up at 3, 6, 9, 12, 15, and 18 months after randomization. The study was performed at 12 sites of the clinical and scientific network of German motor neuron disease centers (ALS/MND‐NET). Eligible patients were randomly assigned (1:1) to receive either HCFD (405kcal/day, 100% fat) or placebo in addition to riluzole (100mg/day). The primary endpoint was survival time, defined as time to death or time to study cutoff date.
Results
Two hundred one patients (80 female, 121 male, age = 62.4 ± 10.8 years) were included. The confirmatory analysis of the primary outcome survival showed a survival probability of 0.39 (95% confidence interval CI = 0.27–0.51) in the placebo group and 0.37 (95% CI = 0.25–0.49) in the HCFD group, both after 28 months (point in time of the last event). The hazard ratio was 0.97, 1‐sided 97.5% CI = −∞ to 1.44, p = 0.44.
Interpretation
The results provide no evidence for a life‐prolonging effect of HCFD for the whole amyotrophic lateral sclerosis population. However, post hoc analysis revealed a significant survival benefit for the subgroup of fast‐progressing patients. ANN NEUROL 2020;87:206–216
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the ...nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.
Targeting C9orf72 in people with ALS Petri, Susanne
Lancet neurology,
September 2024, 2024-09-00, 20240901, Volume:
23, Issue:
9
Journal Article
Peer reviewed
The most common mutations causing familial ALS are hexanucleotide repeat expansions in the intron 1 non-coding region of C9orf72 and mutations in the SOD1, TDP-43, and FUS genes.2,3 Increased ...understanding of the genetic causes of familial ALS, together with advances in molecular therapy, have resulted in the development of novel therapeutic strategies, including the use of antisense oligonucleotides to target C9Orf72; this approach is tested in a phase 1 clinical trial now reported in The Lancet Neurology by Leonard van den Berg and colleagues.4 The antisense oligonucleotide-based treatment tofersen has been shown to reduce concentrations of both wildtype and mutated SOD1 protein in the CSF, to lower serum and CSF levels of neurofilament light chain (the most well studied prognostic disease marker), and ultimately to delay deterioration of muscle and respiratory function in phase 1–3 trials.5 Tofersen has therefore been approved by the US Food and Drug Administration and the European Medicines Agency for treatment of ALS caused by mutations in SOD1 (the second most common form of familial ALS). ...an increase in plasma and CSF neurofilament light chain concentrations in the high dose groups, together with faster clinical decline, led to discontinuation of clinical development of BIIB078 and the open label extension study. In line with these data, a phase 1b/2a trial of another antisense oligonucleotide, also aiming to reduce C9orf72 variant 1 and 3 transcripts (WVE-004), did not have positive effects on functional outcome but rather resulted in faster clinical deterioration and CSF neurofilament increase in the treated cohorts compared with placebo.7 Despite these disappointing results, indicating that BIIB078 is not beneficial for people with C9orf72-associated ALS, the study raises important questions regarding the roles of the C9orf72 antisense transcripts and dipeptide repeats, haploinsufficiency, effects downstream of the repeat expansion, and potential antisense oligonucleotide toxicity.
Previous randomised controlled trials assessing psychological support such as mindfulness-based stress reduction and cognitive behavioural therapy have been limited to rather small patient numbers ...and short observation periods as well as few adequate control groups.4,5 Recommendations for psychological interventions are therefore without reliable evidence and have not been included into current guidelines for the treatment of motor neuron disease.6,7 Rebecca L Gould and colleagues8 now have conducted the largest clinical study on the effect of any type of psychological intervention in amyotrophic lateral sclerosis (ALS) to date, reported in The Lancet. The main result was significantly increased quality of life at 6 months and 9 months post-randomisation in the ACT plus usual care group compared with usual care alone, regardless of pre-existing depression; p=0.0032). Limitations of the study are mainly associated with the specific nature of trials on psychological interventions. Because the control group did not receive any type of treatment in addition to usual care, conclusions regarding specific effects of ACT, as opposed to general effects of the regular provision of attention and support via the sessions, are restricted.
Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak.
Objectives: To provide evidence‐based or expert recommendations for the diagnosis and ...management of ALS based on a literature search and the consensus of an expert panel.
Methods: All available medical reference systems were searched, and original papers, meta‐analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus.
Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non‐invasive positive‐pressure ventilation also improves survival and quality of life. Maintaining the patient’s ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end‐of‐life care should be discussed early with the patient and carers, respecting the patient’s social and cultural background.
OBJECTIVETo examine neurofilament (Nf) concentrations according to symptom onset and clinical diagnostic certainty categories of amyotrophic lateral sclerosis (ALS).
METHODSWe measured Nf light chain ...(NfL) and phosphorylated Nf heavy chain (pNfH) CSF and NfL serum levels in patients with ALS with first symptom onset ≤6 months (n = 54) or >6 months (n = 135) from sampling, and patients with other neurologic diseases, differential diagnoses of a motor neuron disease (MND mimics), and other MND variants to determine the diagnostic accuracy in patients with ALS with early symptom onset. Samples were received multicentric and analyzed by ELISA and Simoa platform and related to other clinical measures.
RESULTSNfL and pNfH in CSF and NfL in serum were increased in early and later symptomatic phase ALS (p < 0.0001). CSF and serum NfL and CSF pNfH discriminated patients with ALS with early symptom onset from those with other neurologic diseases and MND mimics with high sensitivity (94%, 88%, 98%, and 89%, 100%, 78%) and specificity (86%, 92%, 91%, and 94%, 90%, 98%) and did not vary between clinical diagnostic categories of ALS in the early symptomatic phase group. Baseline NfL and pNfH levels were not significantly different in patients with ALS with clinical progression to definite or probable ALS at follow-up.
CONCLUSIONThe measurement of Nf has potential to enhance diagnostic accuracy of ALS in those presenting soon after symptom onset, and is measurable across multiple centers.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregation in the motor neurons. Present and earlier proteomic studies to characterize peptides ...in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target low molecular weight proteins and peptides. We hypothesized that specific changes in CSF peptides or low molecular weight proteins are significantly altered in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions.
Cerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30-40 min after the puncture, and stored at -80°C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography/mass spectrometry (CE-MS/MS or LC-MS/MS).
In the CSF of 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single-pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain.
Most striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found.
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