Limited Assessment of Respiratory Muscle Response to Nusinersen Treatment in Infants with Spinal Muscular Atrophy.
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ABSTRACT:
SUBMITTER: Chacko A
PROVIDER: S-EPMC7047456 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7047463 | biostudies-literature
Project description:BackgroundNeuroinflammation contributes to the onset and progression of neurodegenerative diseases, but has not been specifically investigated in patients affected by severe and milder forms of spinal muscular atrophy (SMA).MethodsIn this two-center retrospective study, we investigated signatures of neuroinflammation in forty-eight pediatric male and female SMA1 (n = 18), male and female SMA2 (n = 19), and female SMA3 (n = 11) patients, as well as in a limited number of male and female non-neurological control subjects (n = 4). We employed a Bio-Plex multiplex system based on xMAP technology and performed targeted quantitative analysis of a wide range of pro- and anti-inflammatory cytokines (chemokines, interferons, interleukins, lymphokines and tumor necrosis factors) and neurotrophic factors in the cerebrospinal fluid (CSF) of the study cohort before and after Nusinersen treatment at loading and maintenance stages.ResultsWe find a significant increase in the levels of several pro-inflammatory cytokines (IL-6, IFN-γ, TNF-α, IL-2, IL-8, IL-12, IL-17, MIP-1α, MCP-1, and Eotaxin) and neurotrophic factors (PDGF-BB and VEGF) in the CSF of SMA1 patients relative to SMA2 and SMA3 individuals, who display levels in the range of controls. We also find that treatment with Nusinersen significantly reduces the CSF levels of some but not all of these neuroinflammatory molecules in SMA1 patients. Conversely, Nusinersen increases the CSF levels of proinflammatory G-CSF, IL-8, MCP-1, MIP-1α, and MIP-1β in SMA2 patients and decreases those of anti-inflammatory IL-1ra in SMA3 patients.ConclusionsThese findings highlight signatures of neuroinflammation that are specifically associated with severe SMA and the neuro-immunomodulatory effects of Nusinersen therapy.
| S-EPMC9932014 | biostudies-literature
Project description:Real-world data have shown mild improvement of overall motor function in adult patients treated with nusinersen, the first approved therapy for 5q-spinal muscular atrophy (SMA). However, knowledge about preferably targeted muscle functions is sparse. The aim of this study was to evaluate strength of distinct muscles and body regions in adult SMA patients in the early course of nusinersen therapy. 72 muscles of 15 patients were tested on the Medical Research Council (MRC) 0-10 scale (translated into MRC %) from nusinersen start to 14 months of treatment. The whole body muscular strength improved slightly or remained stable in 80% of SMA patients with a median improvement of + 2%. However, relevant increases of muscle strength of distinct regions were identified in the proximal upper limbs and shoulder girdle (median + 8%) and in muscle groups with a preserved function pre-treatment, even in more advanced diseased SMA patients. MRC grading was additionally performed in seven patients enrolled during ongoing treatment. Here, further improvement of muscle strength until month 18-26 was seen with the highest increases in the proximal upper and lower limbs. Our findings suggest that sole evaluation of the overall muscle strength might underestimate nusinersen therapy benefits.
| S-EPMC10107562 | biostudies-literature
Project description:The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.
| S-EPMC7998943 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular degenerative disease characterized by loss of spinal cord motor neurons leading to progressive muscle wasting. The most common pathology results from a homozygous disruption in the survival motor neuron 1 (SMN1) gene on chromosome 5q13 via deletion, conversion, or mutation. SMN2 is a near duplicate of SMN1 that can produce full-length SMN mRNA transcripts, but its overall production capability of these mRNA transcripts is lower than that seen in SMN1. This leads to lower levels of functional SMN protein within motor neurons. The FDA approved nusinersen in December 2016 to treat SMA associated with SMN1 gene mutation. It is administered directly to the central nervous system by intrathecal injection. An antisense oligonucleotide (ASO) drug, nusinersen, provides an upcoming and promising treatment option for SMA and represents a novel pharmacological approach with a mechanism of action relevant for other neurodegenerative disorders. Nusinersen begins with four initial loading doses that are followed by three maintenance doses per year. Three major studies (CHERISH, ENDEAR, and NURTURE) have shown to improve motor function in early and late-onset individuals and reduce the chances of ventilator requirements in pre-symptomatic infants. Studies investigating the timing of drug delivery in mouse models of SMA report the best outcomes when drugs are delivered early before any significant motor function is lost. Nusinersen is a novel therapeutic approach with consistent results in all three studies and is proof of the novel concept for treating SMA and other neurodegenerative disorders in the future.
| S-EPMC8567776 | biostudies-literature
Project description:Intrathecal delivery of Nusinersen-an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction-is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.
| S-EPMC9599672 | biostudies-literature
Project description:AimTo gain insight into parents' perspectives about their decision-making process concerning nusinersen treatment for their child, including perceived needs and concerns, and to explore factors that influence this process.MethodThis was an exploratory qualitative interview study among parents of children with spinal muscular atrophy types 1 to 3. Data were analysed using inductive thematic analysis.ResultsNineteen parents of 16 children representing 13 families participated. A wide variety of perspectives was reported ranging from a biomedical approach, which focused on battling the disease, to a holistic approach, which aimed for a good quality of life for their child. The most important factors that helped parents to decide were honest and neutral communication with their physician and access to available information.InterpretationIt is important physicians understand that there are different perspectives influencing the decision-making process. Physicians should create an environment that allows parents to accept or reject treatment by communicating honestly and openly with them and by discussing both options extensively. Clear information about pros and cons, recent developments in research, and the experiences of other parents should be made available to enable parents to make an informed decision. What this paper adds Parents perceived different needs and concerns about nusinersen treatment, which emphasized individual differences. Parents' perspectives varied from battling the disease to preserving quality of life. Life expectancy, stopping deterioration, and improving quality of life were the perceived benefits of nusinersen treatment. Open communication about the pros and cons of treatment with clinicians facilitated decision-making. Clear and honest information facilitated the alignment of values and goals.
| S-EPMC8248060 | biostudies-literature
Project description:BackgroundStudies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen.MethodsIn this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.ResultsCHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.ConclusionsCHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.
| S-EPMC8320162 | biostudies-literature
Project description:Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes of the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and sex-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PDX015117. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.
2020-01-07 | PXD016757 | Pride
Project description:ObjectiveWe report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.MethodsPatients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment.ResultsOver 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.InterpretationOur results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
| S-EPMC8351459 | biostudies-literature