Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.
Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.
复制标题
DOI：
10.1016/j.ajhg.2023.01.019
复制
发表时间：
2023-03-02
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
家族性自主神经功能障碍（FD）是一种罕见的神经退行性疾病，由延伸子乙酰转移酶复合物亚单位1（ELP 1）的剪接突变引起。这种突变导致外显子20的跳跃和ELP 1的组织特异性减少，主要在中枢和外周神经系统中。FD是一种复杂的神经系统疾病，伴有严重的步态共济失调和视网膜变性。目前还没有有效的治疗方法来恢复FD患者的ELP 1生产，这种疾病最终是致命的。在确定激动素是一种能够纠正ELP 1剪接缺陷的小分子后，我们对其进行了优化，以产生可用于FD患者的新型剪接调节剂化合物（SMCs）。在这里，我们优化了第二代激动素衍生物的效力、功效和生物分布，以开发一种可有效通过血脑屏障并纠正神经系统中ELP 1剪接缺陷的FD口服治疗药物。我们证明了新型化合物PTC 258有效地恢复了小鼠组织（包括大脑）中正确的ELP 1剪接，最重要的是，防止了FD特征性的进行性神经元变性。对表型小鼠模型TgFD 9; Elp 1 Δ20/flox出生后经口给予PTC 258以剂量依赖性方式增加全长ELP 1转录物，并导致脑中功能性ELP 1增加2倍。值得注意的是，PTC 258治疗改善了表型FD小鼠的存活率、步态共济失调和视网膜变性。我们的研究结果突出了这种新型小分子作为FD口服治疗的巨大治疗潜力。Morini等人描述了家族性自主神经功能障碍（FD）的口服治疗的优化，这是一种由ELP 1中的剪接突变引起的罕见神经退行性疾病。他们的化合物在包括大脑在内的每一个组织中恢复正确的ELP 1剪接，并在FD小鼠模型中预防步态共济失调和视网膜变性。
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD. Morini et al. describe the optimization of an oral treatment for familial dysautonomia (FD), a rare neurodegenerative disease caused by a splicing mutation in ELP1. Their compound restores correct ELP1 splicing in every tissue, including brain, and prevents gait ataxia and retinal degeneration in a mouse model of FD.
登录
查看更多内容
DOI：
10.1073/pnas.1308596110
发表时间：
2013-11-12
影响因子：
11.1
作者：
George, Lynn;Chaverra, Marta;Lefcort, Frances
通讯作者：
Lefcort, Frances
DOI：
10.1073/pnas.1419045111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Akay, Turgay;Tourtellotte, Warren G.;Jessell, Thomas M.
通讯作者：
Jessell, Thomas M.
影响因子：
3.6
作者：
Axelrod, Felicia B.;Liebes, Leonard;Slaugenhaupt, Susan A.
通讯作者：
Slaugenhaupt, Susan A.
影响因子：
4.2
作者：
Hamers, FPT;Koopmans, GC;Joosten, EAJ
通讯作者：
Joosten, EAJ
影响因子：
3.5
作者：
通讯作者：
--