内源性AAV9-MAG-hABCD1载体逆转成年肾上腺神经病变小鼠的运动缺陷

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Yasemin Özgür Günes, Catherine Le Stunff, Pierre Bougnères
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引用次数: 0

摘要

在世界范围内,成千上万携带ATP结合盒亚家族D成员1 (ABCD1)突变的男性患者在成年中期患上肾上腺髓神经病变(AMN),这是一种使脊髓衰弱的轴索病。今天,AAV基因治疗为这种孤儿病带来了最大的希望。我们之前报道了在新生儿期静脉注射AAV9-MAG-hABCD1载体可以预防2岁的Abcd1-/-小鼠(AMN小鼠模型)的疾病。在目前的研究中,同样的载体在18个月大时被腹腔注射,此时大约有一半的Abcd1-/-小鼠开始失去平衡和运动能力。在注射载体1-3个月后,治疗和未治疗(UT)小鼠的运动测试发生了不同的变化。治疗后6个月,24只小鼠的运动表现接近正常,而34只小鼠的神经状态恶化。在颈脊髓的5个白质区域,hABCD1在24月龄时在22%(18-27)的少突胶质细胞(OLs)和22%(17-26)的星形胶质细胞中表达,而在神经元或小胶质细胞中未检测到。hABCD1在小脑和脑干的OLs和星形胶质细胞中也有大量表达,在脊髓下部也有少量表达,而在背根神经节或脑皮层中没有表达。综上所述,AAV9-MAG-hABCD1载体在Abcd1-/-小鼠早期症状期的作用为AMN的基因治疗开辟了一条新的寡向性途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice.

Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 (ABCD1) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG-hABCD1 vector injected intravenously in the neonatal period prevented the disease in 2-year-old Abcd1-/- mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of Abcd1-/- mice start losing balance and motricity. As soon as 1-3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice (n = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice (n = 34). In five white matter regions of the cervical spinal cord, hABCD1 expression at 24 months of age was present in 22% (18-27) of oligodendrocytes (OLs) and 22% (17-26) of astrocytes and not detected in neurons or microglia. Abundant hABCD1 expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG-hABCD1 vector at an early symptomatic stage of the Abcd1-/- mouse model paves a new oligotropic way for the gene therapy of AMN.

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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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