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Expanding the Availability of Onasemnogene Abeparvovec to Older Patients: The Evolving Treatment Landscape for Spinal Muscular Atrophy

PHARMACEUTICS (2023)

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Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment

Eugenio Mercuri et al.

Summary: The study demonstrated a twofold increase in SMN protein after treatment with risdiplam, suggesting its potential effectiveness in treating spinal muscular atrophy. Additionally, the safety profile of risdiplam supported the continuation of the pivotal Part 2 study.

EUROPEAN JOURNAL OF NEUROLOGY (2023)

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Article Clinical Neurology

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study

Astrid Pechmann et al.

Summary: This study reported data from the SMArtCARE registry of ambulant patients with spinal muscular atrophy (SMA) treated with nusinersen. The results showed a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. Not only did they observe stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

JOURNAL OF NEUROMUSCULAR DISEASES (2023)

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Article Clinical Neurology

Nusinersen for adults with spinal muscular atrophy

Doruk Arslan et al.

Summary: This study presents clinical experience in adult SMA patients treated with nusinersen. Results showed that 78% of patients responded to treatment, with improvements in motor function and mobility observed. ALSFRS-R and 6MWT can be alternative tools to monitor the effectiveness of nusinersen.

NEUROLOGICAL SCIENCES (2023)

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Article Medicine, Research & Experimental

Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route

Chunyan Jia et al.

Summary: Antisense oligonucleotides (ASOs) show promise as therapeutics for CNS diseases, but neurotoxicity is a major limitation. This study used behavioral analysis to evaluate the acute neurotoxicity of toxic ASOs in mice. It was found that toxic ASOs reduced consciousness and locomotor function in a dose-dependent manner, and changes in intracellular free calcium levels were identified as a mechanism underlying the neurotoxic effects of ASO.

MOLECULAR THERAPY-NUCLEIC ACIDS (2023)

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Article Clinical Neurology

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Claudia A. A. Chiriboga et al.

Summary: This study investigated the safety and pharmacodynamics of risdiplam in patients with spinal muscular atrophy (SMA) who had been previously treated. The results showed that the safety and pharmacokinetics of risdiplam in previously treated patients were consistent with treatment-naive patients.

NEUROLOGY AND THERAPY (2023)

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Article Clinical Neurology

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG)

Richard S. Finkel et al.

Summary: This study assessed the safety and efficacy of intrathecal onasemnogene abeparvovec in SMA patients. The results showed that intrathecal administration was safe and effective at an appropriate dose. Older patients showed significant improvement in HFMSE score after treatment.

JOURNAL OF NEUROMUSCULAR DISEASES (2023)

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Article Clinical Neurology

Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report

Cristina Molera et al.

Summary: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by skeletal muscle weakness, respiratory distress, and motor dysfunction. This disease can also be associated with hepatic peliosis, a potentially life-threatening condition. In this study, we report on five XLMTM patients who experienced intrahepatic cholestasis, highlighting the need for further investigation into these manifestations.

JOURNAL OF NEUROMUSCULAR DISEASES (2022)

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Article Clinical Neurology

Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2) : a phase 3, double-blind, randomised, placebo-controlled trial

Eugenio Mercuri et al.

Summary: Risdiplam has shown significant improvement in motor function compared to placebo in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Motor function generally improved in younger patients and stabilized in older patients.

LANCET NEUROLOGY (2022)

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Article Biochemistry & Molecular Biology

Acute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features

Peter H. Hagedorn et al.

Summary: The study utilized antisense oligonucleotides as a new therapeutic modality, identifying a sequence design algorithm through bioinformatics and cell analysis to reduce toxic molecules. A predictive method for behavioral side effects after ICV dosing was developed, guiding future medicinal chemistry efforts.

NUCLEIC ACID THERAPEUTICS (2022)

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Article Pediatrics

Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study

Claudia Weiss et al.

Summary: This study provides real-world data on motor function and safety after gene replacement therapy in different patient subgroups. The results indicate that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored.

LANCET CHILD & ADOLESCENT HEALTH (2022)

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Article Biotechnology & Applied Microbiology

Single-Dose Intrathecal Dorsal Root Ganglia Toxicity of Onasemnogene Abeparvovec in Cynomolgus Monkeys

Francis Fonyuy Tukov et al.

Summary: The intrathecal administration of onasemnogene abeparvovec may be a better option for treating spinal muscular atrophy in later-onset patients. Microscopic changes in the dorsal root ganglion were observed in nonhuman primates following intrathecal administration of onasemnogene abeparvovec. These changes included inflammation and degeneration, but were generally decreased after 52 weeks. Similar microscopic changes were also observed in the intravenous administration group, but to a lesser degree.

HUMAN GENE THERAPY (2022)

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Article Clinical Neurology

Child Neurology: Pathologically Confirmed Thrombotic Microangiopathy Caused by Onasemnogene Abeparvovec Treatment for SMA

Kotaro Yazaki et al.

Summary: This article presents the renal histopathologic findings of drug-induced thrombotic microangiopathy (TMA) due to onasemnogene abeparvovec. The patient's TMA resolved after receiving treatment.

NEUROLOGY (2022)

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Review Biotechnology & Applied Microbiology

Evaluating the state of the science for adeno-associated virus integration: An integrated perspective

Denise E. Sabatino et al.

Summary: This paper reviews the evidence of host genome integration of recombinant AAV (rAAV) in animal models and the potential risks of insertional mutagenesis in patients, highlighting the need for further research, regulatory guidance, and patient care in the field of gene therapy.

MOLECULAR THERAPY (2022)

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Article Biochemistry & Molecular Biology

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial

Kevin A. Strauss et al.

Summary: Onasemnogene abeparvovec was effective and well tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.

NATURE MEDICINE (2022)

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Article Biochemistry & Molecular Biology

Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial

Kevin A. Strauss et al.

Summary: SPR1NT (NCT03505099) is a Phase III study investigating the efficacy and safety of onasemnogene abeparvovec in presymptomatic children with biallelic SMN1 mutations. The results showed that all 14 infants enrolled in the study were able to sit independently for at least 30 seconds within 18 months and none required permanent ventilation. The treatment was well tolerated and effective for children expected to develop SMA type 1.

NATURE MEDICINE (2022)

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Article Clinical Neurology

Research Paper Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program

Deepa H. Chand et al.

Summary: The Global Managed Access Program (GMAP) allowed treatment with Onasemnogene abeparvovec for patients weighing more than 8.5 kg. Safety data for these heavier patients showed consistent results with those reported in clinical trials.

PEDIATRIC NEUROLOGY (2022)

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Article Biotechnology & Applied Microbiology

Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice

Dhwanil A. Dalwadi et al.

Summary: Integration of adeno-associated virus (AAV) into host genomes can lead to hepatocellular carcinoma (HCC), especially when it occurs in oncogenic hotspots. Research has shown that mice exposed to rAAV gene therapy in the context of non-alcoholic fatty liver disease (NAFLD) are more likely to develop HCC, highlighting the potential risk factors associated with rAAV-induced oncogenesis.

MOLECULAR THERAPY (2021)

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Editorial Material Biotechnology & Applied Microbiology

Fourth Boy Dies in Clinical Trial of Astellas' AT132

Alex Philippidis

HUMAN GENE THERAPY (2021)

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Article Clinical Neurology

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial

Eugenio Mercuri et al.

Summary: The STR1VE-EU study evaluated the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, showing effectiveness in symptomatic patients and a favorable benefit-risk profile for this patient population. Further long-term safety studies are needed.

LANCET NEUROLOGY (2021)

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Article Biochemistry & Molecular Biology

Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue

Gretchen Thomsen et al.

Summary: Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration. Both patients experienced varying outcomes after receiving the treatment, including improved motor function in one patient and death in the other shortly after administration. The study demonstrates effective distribution, transduction, and expression of onasemnogene abeparvovec throughout the CNS, supporting its potential for restoring SMN expression in individuals with SMA1.

NATURE MEDICINE (2021)

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Article Gastroenterology & Hepatology

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

Deepa Chand et al.

Summary: This study focuses on the risk of liver injury associated with OA in the treatment of SMA and provides guidance on its management. Analysis of data from 325 patients receiving OA treatment showed elevated liver function test results in some patients. Most patients mitigated these adverse effects through prophylactic prednisolone treatment.

JOURNAL OF HEPATOLOGY (2021)

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Article Medicine, General & Internal

Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I

Andrada Mirea et al.

Summary: The study results suggest that early treatment plays a more significant role in the motor function development of SMA patients, while combination therapy is not more effective than monotherapy.

JOURNAL OF CLINICAL MEDICINE (2021)

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Article Clinical Neurology

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial

John W. Day et al.

Summary: The study evaluated the safety and efficacy of onasemnogene abeparvovec gene therapy in symptomatic patients with infantile-onset spinal muscular atrophy. Results showed that patients achieved independent sitting and survival rates without permanent ventilation at certain time points, with a favorable benefit-risk profile supporting the use of onasemnogene abeparvovec for treatment of this condition.

LANCET NEUROLOGY (2021)

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Article Clinical Neurology

Newborn screening programs for spinal muscular atrophy worldwide: Where we stand and where to go

Tamara Dangouloff et al.

Summary: The study provides a global overview on the current situation and perspectives on SMA NBS, pointing out the differences in funding, screening methods, organization, and consent process between countries. Experts expressed a strong need for the implementation of SMA NBS to improve patient care.

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Article Clinical Neurology

Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

Jerry R. Mendell et al.

Summary: This ongoing study evaluates the long-term safety and effectiveness of onasemnogene abeparvovec gene replacement therapy in infants with SMA type 1. The therapeutic dose showed sustained clinical benefits for patients with no need for permanent ventilation up to 6 years of age.

JAMA NEUROLOGY (2021)

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Review Pharmacology & Pharmacy

Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

Charlotte A. Rene et al.

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PHARMACEUTICS (2021)

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Article Clinical Neurology

Combination therapy with onasemnogene and risdiplam in spinal muscular atrophy type 1

Kelly F. Oechsel et al.

Summary: Combination therapy with onasemnogene and risdiplam in patients with spinal muscular atrophy (SMA) is well-tolerated, with patients experiencing objective and subjective improvement. Further large prospective trials are needed to determine the comparative efficacy of dual therapy over monotherapy, and to identify rare adverse events associated with combination therapy.

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Article Genetics & Heredity

Growth patterns in children with spinal muscular atrophy

Ramona De Amicis et al.

Summary: This study presented growth patterns of treatment-naive SMA1 and SMA2 patients, showing lower body weight and BMI in SMA patients compared to healthy peers, as well as potential implications for clinical management and assessing the efficacy of therapies on both motor function and growth.

ORPHANET JOURNAL OF RARE DISEASES (2021)

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Overturning the Paradigm of Spinal Muscular Atrophy as Just a Motor Neuron Disease

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Intragenic and structural variation in the SMN locus and clinical variability in spinal muscular atrophy

Renske Wadman et al.

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Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Marc-Olivier Deguise et al.

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Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN

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NEW ENGLAND JOURNAL OF MEDICINE (2018)

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Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

Hasane Ratni et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

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NEW ENGLAND JOURNAL OF MEDICINE (2017)

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Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

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Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients

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Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR:: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy

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