Schwann cell gene therapies in sight.
Schwann cell gene therapies in sight.
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DOI：
10.1038/s41434-021-00264-8
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发表时间：
2021-11
期刊：
影响因子：
5.1
通讯作者：
Züchner S
中科院分区：
文献类型：
--
作者：
Züchner S
仅十年前，遗传性周围神经病的药物开发渠道基本上是空的。患者几乎没有选择，自己和孩子的前景也令人沮丧。如今，虽然医生手中仍然没有批准的药物，但一些令人鼓舞的进展，主要是在基因治疗领域，传播了谨慎的乐观情绪。下运动神经元曾经被认为是不可能的治疗目标，其细胞体位于脊髓的腹角，现已成为用于不同基因治疗方法的非常有前途的细胞群。首先，I 型脊髓性肌萎缩症的治疗现已成熟，市场上有多种基因治疗产品。相同的下部运动神经元产生周围神经轴突。这些与许多遗传性疾病有关，以长度依赖性方式影响周围神经。因此，原则上，针对周围神经疾病创建基因疗法应该受益于 FDA 批准的运动神经元疗法所积累的经验。事实上，周围神经的靶向带来了几个具体的挑战，Kagiava 等人的一项研究令人印象深刻地解决了这些挑战。[1]在这个问题上。遗传性周围神经病通常称为夏科-玛丽-图斯病 (CMT)，包括 100 多种遗传定义的孟德尔疾病。总的来说，CMT 是神经病学领域最常见的遗传性疾病之一，患病率为 1-1250 至 1-2500 [2]。据估计，这些患者中的大多数患有脱髓鞘形式，其主要病理生理学是雪旺细胞[3]。雪旺细胞围绕在周围神经中运行的轴突，并形成一种高度专业化的解剖结构，称为髓鞘。髓鞘最极端的形式代表轴突周围一堆致密的层状膜，这对于所有运动神经纤维和一些感觉神经纤维的高信号传导速度至关重要。虽然我们可能并不完全了解雪旺细胞的许多功能，但很明显它们维持了很长的外周轴突的完整性。当雪旺细胞退化时，例如在 1 型 CMT 中，周围神经纤维脱髓鞘，轴突受损，并激活称为华勒变性的死亡过程。生理再生尝试通常是有限的，并导致不规则分层的髓鞘，在组织学切片中可观察到“洋葱球”。雪旺细胞和周围神经轴突在周围神经的神经外膜内形成一个紧密的功能单元，从脊髓根延伸到周围目标。在高个子的人中，最长的周围神经纤维可能有 1000 毫米长——源自腹角的单个核周体。另一个解剖学限制是血/脑或更确切地说血/神经屏障，根据物质的大小和电荷，大多数药物（包括基因疗法）都无法渗透该屏障。因此，将 AAV9 递送至雪旺细胞长期以来一直被认为是一个挑战。卡吉亚瓦等人。关于使用 AAV9 载体开发 CMT 1X 型基因治疗方法的报告 [1]。 CMT1X 是第二常见的遗传性脱髓鞘性神经病，其特征是缓慢进行性远端肌肉无力和萎缩、长度依赖性感觉缺陷、深部腱反射丧失和神经传导速度降低。由于其 X 连锁遗传，CMT1X 主要影响男性，发病年龄为 5-20 岁。女性在以后的生活中可能会出现较轻微的症状。在 CMT1X 功能机制丧失的前提下，GJB1/Cx32 基因构建体被置于……
Only a decade ago, the drug development pipeline for inherited peripheral neuropathies was largely empty. Patients were left with few options and a depressing outlook for themselves and their children. Today, while physicians still do not have approved drugs in hand, a number of encouraging developments, chiefly in the genetic therapy field, spread cautious optimism. Once considered an impossible target for therapies, lower motoneurons, with their cell bodies located in the ventral horn of the spinal cord, have emerged as a highly promising cell population for different gene therapy approaches. Foremost, treatment of spinal muscular atrophy type I is now well-established with several genetic therapy products on the market. The same lower motoneurons give rise to peripheral nerve axons. These are involved in many genetically defined diseases, affecting peripheral nerves in a length-dependent manner. Creating gene therapies for peripheral nerve disorders should therefore, in principle, benefit from the experience gathered by FDA-approved motoneuron therapies. In reality, the targeting of peripheral nerves poses several specific challenges that were impressively addressed in a study by Kagiava et al.[1] in this issue. Inherited peripheral neuropathies, often referred to as Charcot–Marie–Tooth disease (CMT), comprise over 100 genetically defined Mendelian disorders. Collectively, CMT represents one of the most common inherited diseases in the field of neurology with a prevalence of 1–1250 to 1–2500 [2]. By some estimates, the majority of these patients have the demyelinating form, with a primary pathophysiology in Schwann cells [3]. Schwann cells surround axons that run in peripheral nerves and create a highly specialized anatomical structure called the myelin sheath. The myelin sheath, in its most extreme form, represents a stack of densely layered membranes around axons, which are essential for high signal conduction velocity in all motor and some sensory nerve fibers. While we arguably do not fully understand the many functions of Schwann cells, it is clear that they maintain the integrity of the very long peripheral axons. When Schwann cells degenerate, such as in CMT type 1, peripheral nerve fibers are demyelinated, axons are damaged, and a dying-back process is activated known as Wallerian degeneration. Physiological regenerative attempts are usually limited and lead to irregularly layered myelin sheaths observable as “onion bulbs” in histological sections. Schwann cells and peripheral nerve axons form a close functional unit within the epineurium of the peripheral nerve, which extends from the spinal root to the peripheral targets. In tall people, the longest peripheral nerve fibers may be 1000-mm long—emanating from a single perikaryon in the ventral horn. Another anatomical limitation is the blood/brain or rather blood/nerve barrier that, based on size and charge of the substance, is impermeable for most drugs, including gene therapeutics. Thus, delivery of AAV9 to Schwann cells has long been considered a challenge. Kagiava et al. report on the development of a gene therapy approach for CMT type 1X using an AAV9 vector [1]. CMT1X is the second most common inherited demyelinating neuropathy characterized by slowly progressive distal muscle weakness and atrophy, length-dependent sensory deficits, loss of deep tendon reflexes, and reduced nerve conduction velocities. Due to its X-linked inheritance, CMT1X affects mostly men with onset at the age of 5–20 years. Women might develop milder symptoms later in life. Under the premise of a loss of function mechanism in CMT1X, the GJB1/Cx32 gene construct was put …
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DOI：
10.1097/00005072-199907000-00004
发表时间：
1999-07-01
影响因子：
3.2
作者：
Abel, A;Bone, LJ;Fischbeck, KH
通讯作者：
Fischbeck, KH
DOI：
10.1136/jnnp-2014-308826
发表时间：
2015-08
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Fridman V;Bundy B;Reilly MM;Pareyson D;Bacon C;Burns J;Day J;Feely S;Finkel RS;Grider T;Kirk CA;Herrmann DN;Laurá M;Li J;Lloyd T;Sumner CJ;Muntoni F;Piscosquito G;Ramchandren S;Shy R;Siskind CE;Yum SW;Moroni I;Pagliano E;Zuchner S;Scherer SS;Shy ME;Inherited Neuropathies Consortium
通讯作者：
Inherited Neuropathies Consortium
DOI：
10.1523/jneurosci.0325-09.2009
发表时间：
2009-04-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Sargiannidou I;Vavlitou N;Aristodemou S;Hadjisavvas A;Kyriacou K;Scherer SS;Kleopa KA
通讯作者：
Kleopa KA
DOI：
10.1016/j.omtm.2018.02.005
发表时间：
2018-06-15
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Bailey RM;Armao D;Nagabhushan Kalburgi S;Gray SJ
通讯作者：
Gray SJ
影响因子：
2.9
作者：
Bailey RM;Rozenberg A;Gray SJ
通讯作者：
Gray SJ