32 research outputs found

    Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

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    Acknowledgments This study is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (FM and HZ), the Medical Research Council grant (grant reference MR/L013142/1, FM), SMA-Europe grant (FM and HZ) and Great Ormond Street Hospital Children’s Charity grants (FM and HZ). JEM is supported by Great Ormond Street Hospital Children’s Charity. PS is supported by Bill Marshall Fellowship and The CP Charitable Trust at Great Ormond Street Hospital and UCL. SHP is supported by SMA Trust and Euan MacDonald Centre for Motor Neurone Disease Research.Peer reviewedPublisher PD

    Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy

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    BACKGROUND Spinal muscular atrophy (SMA) is caused by genetic defects in the survival motor neuron 1 (SMN1) gene that lead to SMN deficiency. Different SMN‐restoring therapies substantially prolong survival and function in transgenic mice of SMA. However, these therapies do not entirely prevent muscle atrophy and restore function completely. To further improve the outcome, we explored the potential of a combinatorial therapy by modulating SMN production and muscle‐enhancing approach as a novel therapeutic strategy for SMA. METHODS The experiments were performed in a mouse model of severe SMA. A previously reported 25‐mer morpholino antisense oligomer PMO25 was used to restore SMN expression. The adeno‐associated virus‐mediated expression of myostatin propeptide was used to block the myostatin pathway. Newborn SMA mice were treated with a single subcutaneous injection of 40 ÎŒg/g (therapeutic dose) or 10 ÎŒg/g (low‐dose) PMO25 on its own or together with systemic delivery of a single dose of adeno‐associated virus‐mediated expression of myostatin propeptide. The multiple effects of myostatin inhibition on survival, skeletal muscle phenotype, motor function, neuromuscular junction maturation, and proprioceptive afferences were evaluated. RESULTS We show that myostatin inhibition acts synergistically with SMN‐restoring antisense therapy in SMA mice treated with the higher therapeutic dose PMO25 (40 ÎŒg/g), by increasing not only body weight (21% increase in male mice at Day 40), muscle mass (38% increase), and fibre size (35% increase in tibialis anterior muscle in 3 month female SMA mice), but also motor function and physical performance as measured in hanging wire test (two‐fold increase in time score) and treadmill exercise test (two‐fold increase in running distance). In SMA mice treated with low‐dose PMO25 (10 ÎŒg/g), the early application of myostatin inhibition prolongs survival (40% increase), improves neuromuscular junction maturation (50% increase) and innervation (30% increase), and increases both the size of sensory neurons in dorsal root ganglia (60% increase) and the preservation of proprioceptive synapses in the spinal cord (30% increase). CONCLUSIONS These data suggest that myostatin inhibition, in addition to the well‐known effect on muscle mass, can also positively influence the sensory neural circuits that may enhance motor neurons function. While the availability of the antisense drug Spinraza for SMA and other SMN‐enhancing therapies has provided unprecedented improvement in SMA patients, there are still unmet needs in these patients. Our study provides further rationale for considering myostatin inhibitors as a therapeutic intervention in SMA patients, in combination with SMN‐restoring drugs

    Emerging therapies and challenges in Spinal Muscular Atrophy

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    Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368

    Changes in hepatitis A virus (HAV) seroprevalence in medical students in Bangkok, Thailand, from 1981 to 2016

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    Abstract Objective This study aimed to determine the seroprevalence of anti-HAV IgG in Thai medical students in 2016 compared with the previous data and to demonstrate the cross-effective strategy to screen HAV seropositivity. Results Sera from 176 first-year medical students (age 19.07 ± 0.59 years; 50% female) at a university hospital in Thailand were tested for anti-HAV IgG. Data from HAV vaccination records and questionnaires were also collected. HAV seropositivity was unexpectedly high (62.5%, n = 110). 37.5% (n = 66) had an HAV vaccination record. Of these, 60.6% received the full HAV vaccination series, 4.5% received one HAV vaccination, 34.8% did not receive HAV vaccination, and 3.0% had natural HAV immunity. The long-term efficacy of HAV vaccination was at least 97.5% over a mean of 15.55 ± 2.44 years. There was a significant difference in immunity between students with (66.7%) and without (50.9%) vaccination records (P = 0.028). Most of the student’s parents had a bachelor’s degree or higher (87.9%; n = 272) and above average income (mean 17,000.76 ± 194.22 USD/person/year). Parental education and socioeconomic status influenced vaccination accessibility in these medical students. Screening of vaccination records instead of routine anti-HAV IgG testing is a cost-effective and reliable strategy to determine HAV immunity in medical students in Thailand

    Impact of Obesity and Being Overweight on the Immunogenicity to Live Attenuated Hepatitis A Vaccine in Children and Young Adults

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    Prior results investigating a correlation between obesity and hepatitis A virus (HAV) vaccine response have been inconclusive, with limited data involving live attenuated HAV vaccines. The aim of this study is to evaluate the effect of overweight and obesity on the response to live attenuated HAV vaccine in children and young adults. This prospective cohort study was conducted in Thailand with subjects ranging in age from seven to twenty-five years. The subjects were administered 0.5 mL of MEVACℱ-A and tested for anti-HAV antibodies before and at 8–9 weeks after vaccination. Baseline seronegative subjects (anti-HAV antibodies < 20 mIU/mL) were divided into non-obese (underweight/normal weight) and obese (overweight/obesity/severe obesity) groups. A total of 212 (117 non-obese and 95 obese) subjects completed the study (mean age (SD) = 13.95 (3.90) years). The seroprotection rates were 100%. Postvaccination geometric mean titers (95% CI) were 429.51 (401.97, 458.94) and 467.45 (424.47, 514.79) mIU/mL in the non-obese and obese groups, respectively. Females (p = 0.013) and subjects with truncal obesity (p = 0.002) had significantly higher titers than other participants. Live attenuated HAV vaccine is safe and has comparably high immunogenicity in both underweight/normal weight and overweight/obese persons

    Safety and Humoral and Cellular Immunogenicity of the BNT162b2 SARS-CoV-2 Vaccine in Liver-Transplanted Adolescents Compared to Healthy Adolescents

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    Since BNT162b2 was approved to prevent COVID-19 in children, we aim to compare the safety and immunogenicity of the BNT162b2 vaccine in liver-transplanted (LT) and healthy adolescents. LT and healthy adolescents received two doses of 30 ”g of BNT162b2. All were evaluated for total COVID-19 antibodies directed against the receptor-binding domain (RBD) and interferon-Îł using the ELISpot at all time points; anti-nucleocapsid immunoglobulin was evaluated at week 8 and the surrogate virus-neutralizing antibody (sVN) to Omicron at day 0 and week 8. Adverse effects were recorded during days 0–7. In total, 16 LT and 27 healthy adolescents were enrolled (aged 14.78 ± 1.70 years). After completion, all LT and healthy adolescents were positive for anti-RBD immunoglobulin, with geometric mean titers of 1511.37 (95% CI 720.22–3171.59) and 6311.90 (95% CI 4955.46–8039.64)) U/mL (p < 0.001). All tested negative for anti-nucleocapsid immunoglobulin, indicating no COVID-19 infection after vaccination. However, the sVNs to Omicron were positive in only nine (33.33%) healthy adolescents and none of the LT adolescents. Interferon-Îł-secreting cells were lower in LT adolescents than healthy adolescents. The LT adolescents had a lower immunogenic response to BNT162b2 than the healthy adolescents. Administrating two doses of BNT162b2 was safe, but was less effective against the Omicron variant
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