Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

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Antisense Oligonucleotide Therapies for Neurodegenerative Diseases

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-070918-050501 ◽

2019 ◽

Vol 42 (1) ◽

pp. 385-406 ◽

Cited By ~ 41

Author(s):

C. Frank Bennett ◽

Adrian R. Krainer ◽

Don W. Cleveland

Keyword(s):

Neurodegenerative Diseases ◽

Spinal Muscular Atrophy ◽

Antisense Oligonucleotide ◽

Antisense Oligonucleotides ◽

Muscular Atrophy ◽

Neurological Diseases ◽

Great Promise ◽

Disease Symptoms ◽

Therapeutic Platform ◽

Lateral Sclerosis

Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.

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Altered Metabolic Profiles of the Plasma of Patients with Amyotrophic Lateral Sclerosis

Biomedicines ◽

10.3390/biomedicines9121944 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1944

Author(s):

Kuo-Hsuan Chang ◽

Chia-Ni Lin ◽

Chiung-Mei Chen ◽

Rong-Kuo Lyu ◽

Chun-Che Chu ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Area Under The Curve ◽

Support Vector ◽

Therapeutic Effects ◽

Targeted Metabolomics ◽

Svm Algorithm ◽

Als Patients ◽

Normal Controls ◽

Lateral Sclerosis

Currently, there is no objective biomarker to indicate disease progression and monitor therapeutic effects for amyotrophic lateral sclerosis (ALS). This study aimed to identify plasma biomarkers for ALS using a targeted metabolomics approach. Plasma levels of 185 metabolites in 36 ALS patients and 36 age- and sex-matched normal controls (NCs) were quantified using an assay combining liquid chromatography with tandem mass spectrometry and direct flow injection. Identified candidates were correlated with the scores of the revised ALS Functional Rating Scale (ALSFRS-r). Support vector machine (SVM) learning applied to selected metabolites was used to differentiate ALS and NC subjects. Forty-four metabolites differed significantly between ALS and NC subjects. Significant correlations with ALSFRS-r score were seen in 23 metabolites. Six of them showing potential to distinguish ALS from NC—asymmetric dimethylarginine (area under the curve (AUC): 0.829), creatinine (AUC: 0.803), methionine (AUC: 0.767), PC-acyl-alkyl C34:2 (AUC: 0.808), C34:2 (AUC: 0.763), and PC-acyl-acyl C42:2 (AUC: 0.751)—were selected for machine learning. The SVM algorithm using selected metabolites achieved good performance, with an AUC of 0.945. In conclusion, our findings indicate that a panel of metabolites were correlated with disease severity of ALS, which could be potential biomarkers for monitoring ALS progression and therapeutic effects.

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Antisense oligonucleotides

Neurology Genetics ◽

10.1212/nxg.0000000000000323 ◽

2019 ◽

Vol 5 (2) ◽

pp. e323 ◽

Cited By ~ 34

Author(s):

Daniel R. Scoles ◽

Eric V. Minikel ◽

Stefan M. Pulst

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Antisense Oligonucleotide ◽

Antisense Oligonucleotides ◽

Muscular Atrophy ◽

Target Sequence ◽

Spinocerebellar Ataxias ◽

Complementary Oligonucleotide ◽

Disease Modifying ◽

Lateral Sclerosis

There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.

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Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts study

10.1101/2021.06.15.21258262 ◽

2021 ◽

Author(s):

Juan F Vazquez Costa ◽

Monica Povedano ◽

Andres E Nascimento-Osorio ◽

Antonio Moreno Escribano ◽

Solange Kapetanovic Garcia ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Vital Capacity ◽

Rating Scale ◽

Muscular Atrophy ◽

Response To Treatment ◽

Benefit Ratio ◽

Safety And Efficacy ◽

Global Impression Of Change ◽

Lateral Sclerosis

Objective To assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. Methods Patients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available. Results Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild. Conclusions Nusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.

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Correlation Between Maximal Tongue Pressure and Swallowing Function in Spinal and Bulbar Muscular Atrophy

Frontiers in Neurology ◽

10.3389/fneur.2021.704788 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dae-Won Gwak ◽

Seung-Hwan Jung ◽

Yu-Sun Min ◽

Jin-Sung Park ◽

Hee-Jin Cho ◽

...

Keyword(s):

Rating Scale ◽

Muscular Atrophy ◽

Correlation Coefficients ◽

Tongue Pressure ◽

Swallowing Function ◽

Progressive Muscle Weakness ◽

Potential Biomarker ◽

Functional States ◽

Common Manifestation ◽

Lateral Sclerosis

Background: Spinal and bulbar muscular atrophy (SBMA) is an X-lined motor neuron disease characterized by progressive muscle weakness, bulbar palsy, and dysphagia. Dysphagia is associated with tongue weakness, which is a common manifestation of SBMA. This study aimed to investigate the correlations between tongue pressure and dysphagia in patients with SBMA.Materials and Methods: Thirty-nine genetically confirmed SBMA patients underwent a videofluoroscopic swallowing study (VFSS) and tongue pressure assessment. Then, we analyzed the maximal tongue pressure (MTP), oral transit time, penetration-aspiration scale (PAS), videofluoroscopic dysphagia scale (VDS), amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and 6-min walk test (6MWT). Pearson and Spearman correlation coefficients were calculated to analyze the association of the MTP with clinical, swallowing, and functional parameters.Results: In the correlation analysis, MTP was negatively correlated with disease duration (r = −0.396, p = 0.013) and VDS (r = −0.426, p = 0.007), and positively correlated with ALSFRS-R (r = 0.483, p = 0.002) and 6MWT (r = 0.396, p = 0.013). The bulbar (r = 0.367, p = 0.022) and gross motor (r = 0.486, p = 0.002) domains of the ALSFRS-R were correlated with MTP.Conclusion: Tongue pressure assessment can be used as a safe and easy tool to assess swallowing function in SBMA patients. Moreover, MTP reflects functional states, including activities of daily living and gait performance, showing it to be a potential biomarker for physical performance in SBMA.

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Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323822 ◽

2020 ◽

Vol 91 (11) ◽

pp. 1166-1174 ◽

Cited By ~ 1

Author(s):

Lorenzo Maggi ◽

Luca Bello ◽

Silvia Bonanno ◽

Alessandra Govoni ◽

Claudia Caponnetto ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Function ◽

Rating Scale ◽

Muscular Atrophy ◽

Inclusion Criteria ◽

Safety And Efficacy ◽

Spinal Muscular Atrophy Type ◽

Adult Age ◽

Median Change

ObjectiveTo retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).MethodsInclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).ResultsWe included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.ConclusionsOur data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

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Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286419846058 ◽

2019 ◽

Vol 12 ◽

pp. 175628641984605 ◽

Cited By ~ 12

Author(s):

Claudia D. Wurster ◽

René Günther ◽

Petra Steinacker ◽

Jens Dreyhaupt ◽

Kurt Wollinsky ◽

...

Keyword(s):

Rating Scale ◽

Muscular Atrophy ◽

Control Group ◽

Limited Information ◽

Csf Flow ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Significant Difference ◽

And Control

Background: There is limited information on neurochemical markers being used to support and monitor the affection of motoneurons in patients with spinal muscular atrophy (SMA). The objective of this study was to examine neurochemical markers in cerebrospinal fluid (CSF) under treatment with the antisense-oligonucleotide (ASO), nusinersen. Methods: We measured markers of axonal degeneration [neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)] along with basic CSF parameters in 25 adolescent and adult SMA type 2 and 3 patients at baseline and after four intrathecal injections of nusinersen. Neurochemical markers were compared with controls. In addition, neurochemical markers in SMA patients were related to the Hammersmith Functional Rating Scale Expanded (HFMSE). Results: No significant difference in neurofilament (Nf) values was observed between SMA and control group, neither at baseline nor after four injections of nusinersen. NfL, protein and quotients of albumin (Qalb) increased slightly in SMA patients after the fourth injection. The slight increase of NfL could be related to the development of mild CSF flow change. No relations were observed between changes in Nf and HFMSE. Conclusion: We assume that Nf levels in CSF in these patients may result from slow disease progression in this stage of disease, pre-existing loss of motoneurons due to long disease duration besides affection of the LMN only. Therefore, we conclude that Nf levels in CSF do not seem useful as diagnostic and monitoring markers in adolescent and adult SMA type 2 and 3 patients.

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Dissociated leg muscle atrophy in amyotrophic lateral sclerosis/motor neuron disease: the ‘split-leg’ sign

Scientific Reports ◽

10.1038/s41598-020-72887-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Young Gi Min ◽

Seok-Jin Choi ◽

Yoon-Ho Hong ◽

Sung-Min Kim ◽

Je-Young Shin ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Muscle Atrophy ◽

Rating Scale ◽

Muscular Atrophy ◽

Compound Muscle Action Potential ◽

Healthy Controls ◽

Abductor Hallucis ◽

Lateral Sclerosis

Abstract Disproportionate muscle atrophy is a distinct phenomenon in amyotrophic lateral sclerosis (ALS); however, preferentially affected leg muscles remain unknown. We aimed to identify this split-leg phenomenon in ALS and determine its pathophysiology. Patients with ALS (n = 143), progressive muscular atrophy (PMA, n = 36), and age-matched healthy controls (HC, n = 53) were retrospectively identified from our motor neuron disease registry. We analyzed their disease duration, onset region, ALS Functional Rating Scale-Revised Scores, and results of neurological examination. Compound muscle action potential (CMAP) of the extensor digitorum brevis (EDB), abductor hallucis (AH), and tibialis anterior (TA) were reviewed. Defined by CMAPEDB/CMAPAH (SIEDB) and CMAPTA/CMAPAH (SITA), respectively, the values of split-leg indices (SI) were compared between these groups. SIEDB was significantly reduced in ALS (p < 0.0001) and PMA (p < 0.0001) compared to the healthy controls (HCs). SITA reduction was more prominent in PMA (p < 0.05 vs. ALS, p < 0.01 vs. HC), but was not significant in ALS compared to the HCs. SI was found to be significantly decreased with clinical lower motor neuron signs (SIEDB), while was rather increased with clinical upper motor neuron signs (SITA). Compared to the AH, TA and EDB are more severely affected in ALS and PMA patients. Our findings help to elucidate the pathophysiology of split-leg phenomenon.

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Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS

Neurology ◽

10.1212/wnl.0000000000009559 ◽

2020 ◽

Vol 95 (1) ◽

pp. e59-e69 ◽

Cited By ~ 8

Author(s):

Michael Benatar ◽

Lanyu Zhang ◽

Lily Wang ◽

Volkan Granit ◽

Jeffrey Statland ◽

...

Keyword(s):

Sample Size ◽

Rating Scale ◽

Limit Of Detection ◽

Muscular Atrophy ◽

Serum Samples ◽

Neurofilament Light ◽

Baseline Serum ◽

Coefficients Of Variation ◽

Pharmacodynamic Biomarkers ◽

Lateral Sclerosis

ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

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Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients

Genes ◽

10.3390/genes13010084 ◽

2021 ◽

Vol 13 (1) ◽

pp. 84

Author(s):

Alma Osmanovic ◽

Isabel Gogol ◽

Helge Martens ◽

Maylin Widjaja ◽

Kathrin Müller ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Disorder ◽

Muscular Atrophy ◽

Gene Encoding ◽

Pathogenic Variants ◽

Whole Exome ◽

Sporadic Cases ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.

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