ACE-083, a locally-acting TGF-β; superfamily ligand trap, increases muscle mass and strength in a mouse model of Duchenne muscular dystrophy

Pearsall, R. Scott; Widrick, Jeffrey J.; Sako, Dianne; Davies, Monique V.; Hevron, K.; Castonguay, Roselyne; Troy, M.; Grinberg, Asya V.; Cannell, M.; Dagon, Yossi; Kumar, Ravindra

doi:10.1016/j.nmd.2016.06.160

Cited by 4 publications

(2 citation statements)

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“…It has been shown to increase muscle volume as well as peak tetanic force of the injected muscle in wild-type mice as well as in mouse models of myogenic and neurogenic neuromuscular diseases, including mdx (Duchenne muscular dystrophy model), superoxide dismutase 1 (amyotrophic lateral sclerosis model), and trembler-J (Charcot-Marie-Tooth disease model). [3][4][5][6] These studies support clinical development of ACE-083 as a potential treatment for a wide range of neuromuscular disorders, in particular those with focal and/or asymmetric muscle involvement.…”

Section: Accepted 25 February 2018mentioning

confidence: 94%

Locally acting ACE‐083 increases muscle volume in healthy volunteers

et al. 2018

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Introduction: ACE‐083 is a locally acting follistatin‐based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first‐in‐human study examined these effects. Methods: In this phase 1, randomized, double‐blind, placebo‐controlled, dose‐ranging study in healthy postmenopausal women, ACE‐083 (50–200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. Results: Fifty‐eight postmenopausal women were enrolled, 42 ACE‐083 and 16 placebo. No serious adverse events (AE), dose‐limiting toxicities, or discontinuations resulting from AEs occurred. Maximum (mean ± SD) increases in RF and TA muscle volume were 14.5% ± 4.5% and 8.9% ± 4.7%, respectively. No significant changes in mean muscle strength were observed. Discussion: ACE‐083 was well tolerated and resulted in significant targeted muscle growth. ACE‐083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. Muscle Nerve 57: 921–926, 2018

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Section: Accepted 25 February 2018mentioning

confidence: 94%

Locally acting ACE‐083 increases muscle volume in healthy volunteers

et al. 2018

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“…Вследствие достаточно большой распространенности заболевания всегда вставал вопрос о поиске эффективного средства терапии. Был проведен ряд клинических испытаний ингибитора миостатина и β-агонистов, но на сегодняшний день ни в одном из них не доказана эффективность этих препаратов [10][11][12]. Применение пациентами комбинации антиоксидантов не привело к значимым улучшениям в тесте 2-минутной ходьбы, но лабораторные биомаркеры показали изменения в положительную сторону [13].…”

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Development of an approach to knockdown of DUX4 gene by siRNA in myoblasts derived from patients with FSHD

Krivosheeva¹,

Вяхирева²,

Табаков³

et al. 2021

Nauchno-Prakticheskii Zhurnal «Medicinskaia Genetika

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Миодистрофия Ландузи-Дежерина (МЛД) - распространённое наследственное заболевание, вызываемое эктопической экспрессией гена DUX4 в мышечных клетках. Метод подавления экспрессии генов при помощи siРНК зарекомендовал себя как эффективный и безопасный способ генной терапии без вмешательства непосредственно в геном. В данной работе мы продемонстрировали возможность трансфекции миобластов человека целевыми siРНК без ущерба жизнеспособности и дальнейшей дифференцировке этих клеток в миотубы. Также мы показали различия в профиле экспрессии генов-мишеней DUX4 между миобластами, полученными от здоровых людей и от пациентов с МЛД. В дальнейшем эти данные могут помочь при разработке эффективных и специфичных siРНК для терапии МЛД. Facioscapulohumeral dystrophy (FSHD) is a common hereditary disease caused by ectopic expression of the DUX4 gene in muscle cells. The method of suppressing gene expression using siRNA has been shown to be an effective and safe method of gene therapy without interfering directly with the genome. In this work, we demonstrated the possibility of transfecting human myoblasts with targeted siRNAs without compromising the viability and further differentiation of these cells into myotubes. We also showed differences in the expression profile of DUX4 target genes between healthy and patient-derived myoblasts. In the future, these data can be used to develop effective and specific siRNAs for the treatment of FSHD.

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Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms!

Nachit

Leclercq

2019

Clinical Science

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Skeletal muscle is a tissue that represents 30–40% of total body mass in healthy humans and contains up to 75% of total body proteins. It is thus the largest organ in non-obese subjects. The past few years have seen increasing awareness of the prognostic value of appreciating changes in skeletal muscle compartment in various chronic diseases. Hence, a low muscle mass, a low muscle function and muscle fatty infiltration are linked with poor outcomes in many pathological conditions. In particular, an affluent body of evidence links the severity, the complications and mortality of chronic liver disease (CLD) with skeletal muscle depletion. Yet it is still not clear whether low muscle mass is a cause, an aggravating factor, a consequence of the ongoing disease, or an epiphenomenon reflecting general alteration in the critically ill patient. The mechanisms by which the muscle compartment influences disease prognosis are still largely unknown. In addition, whether muscle alterations contribute to liver disease progression is an unanswered question. Here, we first review basic knowledge about muscle compartment to draw a conceptual framework for interpreting skeletal muscle alteration in CLD. We next describe recent literature on muscle wasting in cirrhosis and liver transplantation. We then discuss the implication of skeletal muscle compartment in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), focusing on plausible metabolic disruption in muscle compartment that might participate in NAFLD progression. Finally, we discuss shortcomings and challenges we need to address in the near future prior to designate the muscle compartment as a therapeutic target in CLD.

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ACE-083, a locally-acting TGF-β; superfamily ligand trap, increases muscle mass and strength in a mouse model of Duchenne muscular dystrophy

Cited by 4 publications

References 0 publications

Locally acting ACE‐083 increases muscle volume in healthy volunteers

Locally acting ACE‐083 increases muscle volume in healthy volunteers

Development of an approach to knockdown of DUX4 gene by siRNA in myoblasts derived from patients with FSHD

Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms!

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