有一点心脏(或没有):骨骼肌调节盒的活性高度减弱,而心脏的活性很低或没有。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Human gene therapy Pub Date : 2024-08-01 Epub Date: 2024-07-19 DOI:10.1089/hum.2024.041
Charis L Himeda, Takako I Jones, Peter L Jones
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引用次数: 0

摘要

腺相关病毒(AAV)介导的用于治疗某些肌肉疾病的基因疗法需要能提供高水平横纹肌特异性活性的调控盒。然而,在杜氏肌营养不良症和 X 连锁肌管肌病的临床试验中,心脏毒性已成为一个严重问题。虽然这可能是由治疗的全身炎症效应引起的,但心脏中转基因的高表达也可能是原因之一。因此,某些肌肉疾病可能需要在心脏中调节治疗表达水平,而另一些疾病可能根本不需要在心脏中表达。此外,某些载体的大小要求调控盒足够小,以便容纳大的 cDNA 和其他治疗载荷。因此,我们对增强子/启动子进行了优化,以开发在骨骼肌中具有活性,而在心肌中活性较低或无法检测到的高度最小化的调控盒。我们的 "无心"(NH)调控盒在大多数骨骼肌中都有活性,但在伸肌(EDL)、比目鱼肌和膈肌中只有很低的活性,在心脏中没有活性。相比之下,我们的 "有一个小心脏"(HLH)基因盒在大多数骨骼肌中表现出较高的活性,与约 800 位点的 CK8 基因盒相当,在伸肌、比目鱼肌和膈肌中的活性较高,而在心脏中的活性较低。由于其体积小,这些基因盒可用于具有灵活(如反义)和严格(如 CRISPR/Cas 或双螺旋)体积限制的治疗策略。因此,我们的新基因盒可用于肌肉疾病的基因疗法,在这种疗法中,心肌中低表达或几乎不表达的需要将超过某些骨骼肌中高水平治疗产物的需要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Have a Little Heart (or Not): Highly Minimized Skeletal Muscle Regulatory Cassettes with Low or No Activity in the Heart.

Adeno-associated virus-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role. Thus, certain muscle disorders may require a modulated level of therapeutic expression in the heart, while others may not require any cardiac expression at all. Additionally, the size of some cargos requires regulatory cassettes to be small enough that large cDNAs and other therapeutic payloads can be accommodated. Thus, we have performed enhancer/promoter optimization to develop highly minimized regulatory cassettes that are active in skeletal muscles, with either low or no detectable activity in cardiac muscle. Our No-heart (NH) cassette is active in most skeletal muscles, but exhibits only very low activity in extensor digitorum longus (EDL), soleus, and diaphragm, and no activity in the heart. By contrast, our Have a Little Heart (HLH) cassette displays high activity in most skeletal muscles, comparable to the ∼800-bp CK8 cassette, with increased activity in EDL, soleus, and diaphragm, and low activity in the heart. Due to their small size, these cassettes can be used in therapeutic strategies with both flexible (e.g., antisense) and stringent (e.g., CRISPR/Cas or bicistronic) size limitations. Thus, our new cassettes may be useful for gene therapies of muscle disorders in which the need for low or almost no expression in cardiac muscle would outweigh the need for high levels of therapeutic product in certain skeletal muscles.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
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