scholarly journals Disease-modifying immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in young boys with Duchenne muscular dystrophy: Results of an open-label, prospective, randomized, comparative clinical study

2021 ◽  
Author(s):  
Kadalraja Raghavan ◽  
Vidyasagar Devaprasad Dedeepiya ◽  
Subramaniam Srinivasan ◽  
Subramanian Pushkala ◽  
Sudhakar Subramanian ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Aureobasidium Pullulans ◽  
Control Group ◽  
Negative Group ◽  
Tgf Beta ◽  
Beta Glucan ◽  
Study Results ◽  
Disease Modifying

Background: Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder causing progressive muscle weakness and premature death. Steroids remain the mainstream approach for supportive care but have side effects; other targeted therapies and gene therapies are also being developed. As there is limited evidence on the use of disease modifying nutritional supplement adjuncts in DMD, this pilot trial is to evaluate the effects of supplementation of Aureobasidium pullulans-derived 1,3 1,6 beta glucan from the N163 strain in young patients with DMD. Methods: Twenty-seven patients with Duchenne muscular dystrophy (DMD), nine in the control arm (undergoing conventional therapies) participated. The patients were divided into groups: those not administered steroids (Steroid negative) (n = 5), those administered steroids (Steroid positive) (n = 4), and 18 in the treatment arm (N163 beta glucan supplement along with conventional therapies; N-163 Steroid negative and N-163 Steroid positive); they participated in the study for 45 days. Assessments of muscle function, disease status, and levels of IL6, IL13, TGF beta;, creatinine kinase (CK), titin, TNF Alpha;, haptoglobin, and dystrophin in the blood and myoglobin in the urine were performed at baseline and at the end of the study. Results: IL6 showed a significant decrease in the N163 Steroid negative group, from a baseline value of 7.2 pg/ml to 2.7 pg/ml. IL13 decreased in both treatment groups, from 157.76 pg/ml to 114.08 pg/ml (N-163 Steroid negative) and from 289.56 pg/ml to 255.56 pg/ml (N-163 Steroid positive). TGF beta levels showed a significant decrease in the N163 Steroid negative group, from a baseline value of 3302 ng/ml to 1325.66 ng/ml post intervention. Dystrophin levels increased by up to 32% in both Steroid positive and negative groups. Medical research council (MRC) grading showed muscle strength improvement in 12 out of 18 patients (67%) in the treatment group and four out of nine (44%) subjects in the control group. Conclusion: Supplementation with the N163 beta glucan food supplement produced disease-modifying beneficial effects: a significant decrease in inflammation and fibrosis markers, increase in dystrophin and improvement in muscle strength in DMD subjects over 45 days, thus making this a potential adjunct treatment for DMD after validation. A longer duration of follow up and further research on the mechanism of action and commonalities with other diseases provoked by hyperactive inflammation and/or fibrosis may pave the way for their extended applications in other dystrophinopathies and neuroinflammatory diseases.

scholarly journals Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial

2021 ◽  
pp. 1-13
Author(s):  
Craig M. McDonald ◽  
Perry B. Shieh ◽  
Hoda Z. Abdel-Hamid ◽  
Anne M. Connolly ◽  
Emma Ciafaloni ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Natural History ◽  
Adverse Events ◽  
Exon Skipping ◽  
Control Group ◽  
Phase 2 ◽  
Open Label ◽  
M Phase ◽  
Positive Treatment

Background Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. Objective To report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort. Methods Ambulatory patients aged 7–16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled. Results 78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: –68.9 m; phase 2 studies: –67.3 m; external controls: –133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: –3.3%, phase 2 studies: –2.2%, external controls: –6.0%; p <  0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation. Conclusions This large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.

scholarly journals Noninvasive evaluation of respiratory muscles in pre-clinical model of Duchenne Muscular Dystrophy

2016 ◽  
Vol 36 (4) ◽  
pp. 290-296
Author(s):  
Daniela M. Oliveira ◽  
Stefano C. Hagen ◽  
Amilton C. Santos ◽  
Maria A. Miglino ◽  
Antônio C. Assis Neto
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Respiratory Muscles ◽  
Experimental Models ◽  
Noninvasive Evaluation ◽  
Control Group ◽  
Clinical Model ◽  
Intercostal Muscles ◽  
Invasive Method ◽  
Clinical Conditions

Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD), the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD) employing ultrasonography (US). A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility) were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

scholarly journals Autonomic modulation at rest and in response to postural change in adolescents with Duchenne muscular dystrophy: a cross-sectional study

2021 ◽  
Vol 79 (9) ◽  
pp. 766-773
Author(s):  
Mariana Viana Rodrigues ◽  
Mileide Cristina Stoco-Oliveira ◽  
Talita Dias da Silva ◽  
Celso Ferreira ◽  
Heloisa Balotari Valente ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Oxygen Saturation ◽  
Cross Sectional Study ◽  
Control Group ◽  
Autonomic Modulation ◽  
Postural Change ◽  
Cross Sectional

ABSTRACT Background: Analysis of autonomic modulation after postural change may inform the prognosis and guide treatment in different populations. However, this has been insufficiently explored among adolescents with Duchenne muscular dystrophy (DMD). Objective: To investigate autonomic modulation at rest and in response to an active sitting test (AST) among adolescents with DMD. Methods: Fifty-nine adolescents were included in the study and divided into two groups: 1) DMD group: adolescents diagnosed with DMD; 2) control group (CG): healthy adolescents. Participants’ weight and height were assessed. Lower limb function, motor limitations and functional abilities of the participants in the DMD group were classified using the Vignos scale, Egen classification and motor function measurement, respectively. The following variables were assessed before, during and after AST: systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate (f), oxygen saturation and heart rate (HR). To analyze the autonomic modulation, the HR was recorded beat-by-beat. Heart rate variability (HRV) indices were calculated in the time and frequency domains. Results: Differences in relation to groups were observed for all HRV indices, except LF/HF, oxygen saturation, HR and f (p < 0.05). Differences in relation to time and the interaction effect between group and time were observed for RMSSD, SD1, SD2, SD1/SD2, LFms2 and LFnu, HFun, SBP and DBP (p < 0.05). Differences in relation to time were also observed for the indice SDNN, FC and f (p < 0.05). Conclusions: Performing the AST promoted reduced autonomic modulation and increased SBP, DBP and HR in adolescents with DMD.

scholarly journals Mast cells in the pathophysiology of Duchenne muscular dystrophy in Golden Retriever dogs

2020 ◽  
Vol 40 (10) ◽  
pp. 791-797
Author(s):  
Isabela M. Martins ◽  
Lygia M.M. Malvestio ◽  
Jair R. Engracia-Filho ◽  
Gustavo S. Claudiano ◽  
Flávio R. Moraes ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Mast Cells ◽  
Muscular Dystrophy ◽  
Fibrous Tissue ◽  
Control Group ◽  
Golden Retriever ◽  
Collagenous Tissue ◽  
Muscle Types ◽  
Muscle Groups

ABSTRACT: The Golden Retriever muscular dystrophy (GRMD) is one of the best models of Duchenne muscular dystrophy (DMD), with similar genotypic and phenotypic manifestations. Progressive proliferation of connective tissue in the endomysium of the muscle fibers occurs in parallel with the clinical course of the disease in GRMD animals. Previous studies suggest a relationship between mast cells and the deposition of fibrous tissue due to the release of mediators that recruit fibroblasts. The aim of this study was to evaluate the presence of mast cells and their relationship with muscle injury and fibrosis in GRMD dogs of different ages. Samples of muscle groups from six GRMD and four control dogs, aged 2 to 8 months, were collected and analyzed. The samples were processed and stained with HE, toluidine blue, and Azan trichrome. Our results showed that there was a significant increase in infiltration of mast cells in all muscle groups of GRMD dogs compared to the control group. The average number of mast cells, as well as the deposition of fibrous tissue, decreased with age in GRMD dogs. In the control group, all muscle types showed a significant increase in the amount of collagenous tissue. This suggests increased mast cell degranulation occurred in younger GRMD dogs, resulting in increased interstitial space and fibrous tissue in muscle, which then gradually decreased over time as the dogs aged. However, further studies are needed to clarify the role of mast cells in the pathogenesis of fibrosis.

Neck flexor muscle strength and its relation with functional performance in Duchenne muscular dystrophy

2017 ◽  
Vol 21 (3) ◽  
pp. 494-499
Author(s):  
Sibel Bozgeyik ◽  
İpek Alemdaroğlu ◽  
Numan Bulut ◽  
Öznur Yılmaz ◽  
Ayşe Karaduman
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Functional Performance ◽  
Flexor Muscle

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Cathleen E. Buckon ◽  
Susan E. Sienko ◽  
Eileen G. Fowler ◽  
Anita M. Bagley ◽  
Loretta A. Staudt ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Genetic Disorder ◽  
Knee Extensor ◽  
Standard Of Care ◽  
Rate Of Change ◽  
Isokinetic Dynamometry ◽  
Gross Motor

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7–13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. Objective: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. Methods: Eighty-four ambulatory boys with DMD (49–180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. Results: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. Conclusion: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

scholarly journals Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy

2019 ◽  
Vol 28 (16) ◽  
pp. 2686-2695 ◽  
Author(s):  
Pamela Barraza-Flores ◽  
Tatiana M Fontelonga ◽  
Ryan D Wuebbles ◽  
Hailey J Hermann ◽  
Andreia M Nunes ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Premature Death ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Mdx Mouse ◽  
Protein Therapy ◽  
Muscle Fibrosis ◽  
Dog Model

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked disease affecting ~1 in 5000 males. DMD patients exhibit progressive muscle degeneration and weakness, leading to loss of ambulation and premature death from cardiopulmonary failure. We previously reported that mouse Laminin-111 (msLam-111) protein could reduce muscle pathology and improve muscle function in the mdx mouse model for DMD. In this study, we examined the ability of msLam-111 to prevent muscle disease progression in the golden retriever muscular dystrophy (GRMD) dog model of DMD. The msLam-111 protein was injected into the cranial tibial muscle compartment of GRMD dogs and muscle strength and pathology were assessed. The results showed that msLam-111 treatment increased muscle fiber regeneration and repair with improved muscle strength and reduced muscle fibrosis in the GRMD model. Together, these findings support the idea that Laminin-111 could serve as a novel protein therapy for the treatment of DMD.

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