Citations

AbstractBackgroundAchalasia‐addisonianism‐alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD‐repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction.MethodsWhole‐exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant.ResultsFunctional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow‐up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants.ConclusionsReview of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.

AbstractIntroduction/AimsALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C‐reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial.MethodsThe phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs‐CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS‐R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS‐R score over 6 mo (non‐progressor).ResultsThe phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS‐R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40‐ to 65‐y‐old subset in which NP001‐treated patients demonstrated slower declines in ALSFRS‐R score by 36% and VC loss by 51% compared with placebo. A greater number of non‐progressors were NP001‐treated compared with placebo (p = .004).DiscussionAlthough the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS‐R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.

AbstractObjectiveDual leucine zipper kinase (DLK), which regulates the c‐Jun N‐terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first‐in‐human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC‐0134, a small‐molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC‐0134‐treated ALS patients and DLK conditional knockout (cKO) mice.MethodsThe study included placebo‐controlled, single and multiple ascending‐dose (SAD; MAD) stages, and an open‐label safety expansion (OLE) with adaptive dosing for up to 48 weeks.ResultsForty‐nine patients were enrolled. GDC‐0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug‐related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC‐0134 exposure was dose‐proportional (median half‐life = 84 h). Patients showed GDC‐0134 exposure‐dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild‐type littermates.InterpretationThis trial characterized GDC‐0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC‐0134‐treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on‐target drug effects. The safety profile of GDC‐0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

AbstractBackgroundMultiple myeloma (MM) measurable residual disease (MRD) evaluated by flow cytometry is a surrogate for progression‐free and overall survival in clinical trials. However, analysis and reporting between centers lack uniformity. We designed and evaluated a consensus protocol for MM MRD analysis to reduce inter‐laboratory variation in MM MRD reporting.MethodsSeventeen participants from 13 countries performed blinded analysis of the same eight de‐identified flow cytometry files from patients with/without MRD using their own method (Stage 1). A consensus gating protocol was then designed following survey and discussions, and the data re‐analyzed for MRD and other bone marrow cells (Stage 2). Inter‐laboratory variation using the consensus strategy was reassessed for another 10 cases and compared with earlier results (Stage 3).ResultsIn Stage 1, participants agreed on MRD+/MRD− status 89% and 68% of the time respectively. Inter‐observer variation was high for total numbers of analyzed cells, total and normal plasma cells (PCs), limit of detection, lower limit of quantification, and enumeration of cell populations that determine sample adequacy. The identification of abnormal PCs remained relatively consistent. By consensus method, average agreement on MRD− status improved to 74%. Better consistency enumerating all parameters among operators resulted in near‐unanimous agreement on sample adequacy.ConclusionUniform flow cytometry data analysis substantially reduced inter‐laboratory variation in reporting multiple components of the MM MRD assay. Adoption of a harmonized approach would meet an important need for conformity in reporting MM MRD for clinical trials, and wider acceptance of MM MRD as a surrogate clinical endpoint.

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.

Abstract Introduction/Aims Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. Method We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019‐related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. Results Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output ( P < .01). Change could be detected in the larger 4 mg group ( P = .02), but not in the smaller 8 mg dose group ( P = .1). No side effects were reported after single dose exposure. Discussion This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.

Abstract Numerous reports have suggested that infectious agents could play a role in neurodegenerative diseases, but specific etiological agents have not been convincingly demonstrated. To search for candidate agents in an unbiased fashion, we have developed a bioinformatic pipeline that identifies microbial sequences in mammalian RNA-seq data, including sequences with no significant nucleotide similarity hits in GenBank. Effectiveness of the pipeline was tested using publicly available RNA-seq data and in a reconstruction experiment using synthetic data. We then applied this pipeline to a novel RNA-seq dataset generated from a cohort of 120 samples from amyotrophic lateral sclerosis patients and controls, and identified sequences corresponding to known bacteria and viruses, as well as novel virus-like sequences. The presence of these novel virus-like sequences, which were identified in subsets of both patients and controls, were confirmed by quantitative RT-PCR. We believe this pipeline will be a useful tool for the identification of potential etiological agents in the many RNA-seq datasets currently being generated.