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Alk5 inhibitors as skeletal muscle hypertrophy inducers

An inhibitor, skeletal muscle technology, applied in the field of ALK5 inhibitor of skeletal muscle hypertrophy inducer, can solve the problem that there is no specific treatment to stop or reverse muscular dystrophy

Pending Publication Date: 2020-10-30
赛途公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Treatment of neuromuscular disorders depends on the disease and the specific cause, however, to date, there is no specific treatment to stop or reverse any form of muscular dystrophy

Method used

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  • Alk5 inhibitors as skeletal muscle hypertrophy inducers
  • Alk5 inhibitors as skeletal muscle hypertrophy inducers
  • Alk5 inhibitors as skeletal muscle hypertrophy inducers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Materials and methods

[0186] Cell Sources and Cell Culture

[0187] Healthy donor primary skeletal cells (Donor 1, Donor 3, and Donor 5) were Clonetics TM Human skeletal muscle myoblasts (HSMM). In addition, cells were derived from three DMD (Duchenne muscular dystrophy) donors (donors Z, W and D1) and a healthy donor (donor A).

[0188] Donor characteristics are detailed in Table 1 below.

[0189] Table 1: Donor Characteristics

[0190]

[0191]

[0192] Muscle cell cultures were maintained with supplements and fetal bovine serum (FBS) serum provided by Lonza following the supplier's instructions. An expansion step is performed to obtain enough cells to seed selection plates.

[0193] Hypertrophy Assay and Atrophy Rescue Assay

[0194] Using a file called MyoScreen TM Hypertrophy assays and atrophy rescue assays were performed on an in vitro fully automated human myotube model (Cytoo, France). This model relies on tight control of the microenviron...

Embodiment 2

[0236] Example 2: Acetylcholine Receptor Clustering Assay

[0237] Materials and methods

[0238] Perform MyoScreen as described in the hypertrophy and atrophy rescue assay described in Example 1 TMregimen, but discontinued on day 9 instead of day 6. At the end of the assay, AchR was immunostained using specific antibodies in addition to troponin T and nuclei. Images were acquired at ×20 using a Perkin Elmer Operetta high-content imaging system. Image processing and analysis were performed using dedicated algorithms developed on Acapella high-content imaging software (Perkin Elmer). Specific readouts were calculated for each well: nuclei count and myotube fusion index, AchR number, AchR average area, total AchR area normalized by total myotube area.

[0239] result

[0240] Notably, when labeled with a specific anti-AChR antibody, MyoScreen myotubes 6 days after differentiation showed that AChR clusters were interrupted from time to time along the sarcolemma at differ...

Embodiment 3

[0241] Example 3: Calcium flux assay

[0242] Materials and methods

[0243] The cells were washed with a calcium buffer containing (in mM): 130 NaCl, 5.4 KCl, 1.8 CaCl2, 0.8 MgCl2, 5.6 D-glucose, 10 Hepes, pH 7.4. Cells were then incubated with 2 μM Fluo-4 AM (F14201-Invitrogen) for 1 hour in an incubator (37° C., 5% CO 2 ). Myotube responses to 20 μM ACh (A6625-Sigma-Aldrich) will be video imaged after washing to remove unloaded dye. The interval of Streamacquisitions was set to 1 second, and one field of view was collected per well. Images were processed and analyzed automatically using proprietary software developed in-house that incorporates the open source ImageJ framework. This image analysis tool segments myotubes within images acquired in the same well. The total Fluo-4 fluorescence intensity inside each myotube was measured and corrected for background. Total intensity was normalized to myotube area to obtain mean fluorescence intensity readings. For data pre...

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Abstract

The present invention relates to ALK5 inhibitors and their uses as skeletal muscle hypertrophy inducers as well as to promote skeletal muscle regeneration, to prevent skeletal muscle atrophy, or in the treatment or prevention of a disease or injury resulting in loss of skeletal muscle tissue and / or muscle weakness. It further relates to the non-therapeutic use of such compounds to increase musclemass, muscle strength and / or muscle performance in a subject.

Description

technical field [0001] The present invention relates to therapeutic strategies for inducing skeletal muscle hypertrophy, preventing atrophy, or treating or preventing diseases or injuries that result in loss of skeletal muscle tissue and / or muscle weakness. The present invention also relates to non-therapeutic uses of inducers of skeletal muscle hypertrophy. Background technique [0002] Numerous disease states and conditions, including metabolic disease, neurological disease, muscle disease, acute or chronic illness (cachexia), aging, inactivity, food deprivation, and even intoxication, can cause muscle wasting and muscle weakness. Over the past 15 years, extensive research has led to a better understanding of the signaling pathways involved in muscle mass loss. However, to date, the availability of therapeutic strategies that directly target muscles remains poor. [0003] Muscle loss can occur particularly with aging and is a component of frailty syndromes. Known as "sa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/4375A61K31/4439A61K31/4709A61K31/496A61K31/517A61K31/519A61K31/56A61K31/573A61K31/58A61P21/00
CPCA61K31/4375A61K31/4439A61K31/4709A61K31/496A61K31/517A61K31/519A61K31/56A61K31/573A61K31/58A61K45/06A61P21/00A61K2300/00A61K31/444A61K31/498
Inventor 保琳·普瓦德诺约里斯·米肖梅拉妮·福利恩德尔伊夫·迪舍曼-佩尔蒂埃吕克·塞利格
Owner 赛途公司
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