Background
Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training ...(RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS.
Methods
Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health‐related QOL were assessed pre‐post intervention.
Results
RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass.
Conclusions
RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Repetitive Transcranial Magnetic Stimulation (rTMS) is known to modulate cortical excitability and has thus been suggested to be a therapeutic approach for improving the efficacy of rehabilitation ...for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of transcallosal inhibitory pathways between motor primary areas in both hemispheres: the affected hemisphere (AH) may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere, further reducing the excitability of the AH. Conceptually, therefore, rTMS could be used therapeutically to restore the balance of interhemispheric inhibition after stroke. rTMS has been used in two ways: low-frequency stimulation (≤1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or high-frequency stimulation (>1 Hz) to the motor cortex of the AH to increase excitability of the ipsilesional hemisphere. The purpose of this systematic review is to collate evidence regarding the safety and efficacy of high-frequency rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. This review suggests that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. Although the studies included in this review provide important information, double-blinded, sham-controlled Phase II and Phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.
Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic ...modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency ADA-SCID in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy SMA; Duchenne muscular dystrophy DMD; X-linked myotubular myopathy XLMTM; and diseases of the central nervous system, including Alzheimer’s disease, Parkinson’s disease, Canavan disease, aromatic l-amino acid decarboxylase AADC deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration AMD, choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.
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Researchers have been trying to develop therapies for hereditary diseases for more than 30 years. Several problems have been successfully resolved and thus Tremblay and colleagues are describing the recent progress of clinical applications of gene therapy. There are now several in vivo treatments under trials, and some approved for commercialization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox ...balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA.
Methods
We conducted an international, double‐blind, randomized, placebo‐controlled, parallel‐group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015‐002762‐23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.
Results
One hundred fifty‐five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (−1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of –2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.
Interpretation
In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212–225
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pompe disease is a progressive lysosomal storage disorder resulting from deficiency in the lysosomal enzyme acid α‐glucosidase (GAA). The only approved treatment is human recombinant GAA (enzyme ...replacement therapy) which does not cross the blood brain barrier and thus does not mitigate central nervous system pathology. Lingual dysfunction is prominent, leading to common impairments such as dysphagia, dysarthria, and/or disordered breathing. Towards the goal of new treatments that address the underlying neural pathology of lingual impairment, we tested the hypothesis that a single intramuscular delivery of adeno‐associated virus (AAV) encoding GAA delivered to the tongue can drive GAA expression throughout lingual myofibers and associated hypoglossal motoneurons in a rat model of Pompe disease. In addition, we evaluated immune response to the transgene product and sought to determine if an FDA‐approved immunosuppressive drug which inhibits T‐cell activation (Abatacept®) can enhance the efficacy of gene transfer. Experiments were completed using a Gaa‐/‐ rat model of Pompe disease that recapitulates many aspects of the clinical condition. An immunosuppression group (n=3) received three loading doses of Abatacept (10mg/kg) via tail vein 30 days, 14 days, and 1 day prior to intralingual injection of rAAV9‐des‐hGAA (100µl, 1.55x1013 vg/ml) followed by a maintenance dose 30 days later. Blood and serum samples were taken at 3, 7, 14, 30, and 60 days after AAV9 injection and tongue and brainstem tissues were harvested after 60 days. Immunohistochemistry and blood assay results were compared to Pompe rats receiving gene therapy without immunosuppression (n=3), sham injection (n=3) and “wild type” control rats (n=3). Immunohistochemistry with anti‐GAA antibodies unequivocally confirmed that lingual rAAV9‐des‐hGAA delivery drove GAA expression in tongue and hypoglossal motoneurons. In addition, Periodic Acid Shiff (PAS) staining revealed decreased glycogen accumulation in tissues in which GAA immunostaining was prominent. Initial qualitative assessment suggests that Abatacept treatment increases gene therapy efficacy. Anti‐GAA IgG assay results indicate that Abatacept significantly blunted the immune response to the GAA transgene product at 14 days (f(4)= 6.021, p=0.002) but not 30 days post injection (f(4)=6.021, p=0.0736). Lingual injection with rAAV9‐des‐hGAA results in GAA protein expression and glycogen clearance in the tongue as well as the hypoglossal nucleus in animals with Pompe disease. The immunosuppression regimen tested here blunted the initial immune response to the transgene product, and this may have therapeutic benefit. However, modification of this immunosuppression regimen by providing additional maintenance doses may be required for maximal benefit. These data represent a significant step toward a new clinically viable treatment for lingual dysfunction. The results show conclusively that lingual gene therapy can drive expression of a therapeutic protein to correct brainstem and tongue muscle histopathology in a rat model of Pompe disease, and indicate possible additional benefit of immunosuppression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle ...is well characterized, recent research has highlighted critical metabolic and non‐metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n‐GSDs). n‐GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late‐onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n‐GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.
Glycogen is an essential carbohydrate storage molecule involved in multiple tissue‐specific processes. This review provides a comprehensive summary of our understanding of brain glycogen and the multifaceted roles of glycogen proposed by recent articles. The roles are described in health and disease with a focus on current evidence linking glycogen and glycosylation. Finally, we highlight the therapeutic potential of targeting glycogen metabolism and potential avenues for future research.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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