Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
Am J Hum Genet. 2023 Mar 2;110(3):531-547. doi: 10.1016/j.ajhg.2023.01.019. Epub 2023 Feb 20.
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;Elp1 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.
家族性自主神经异常症（FD）是一种罕见的神经退行性疾病，由延伸因子乙酰转移酶复合物亚基 1（ELP1）剪接突变引起。该突变导致外显子 20 跳跃，ELP1 在中枢和外周神经系统中特异性减少，主要在中枢和外周神经系统中减少。FD 是一种复杂的神经疾病，伴有严重的步态共济失调和视网膜变性。目前，没有有效的治疗方法可以恢复 FD 个体中 ELP1 的产生，并且该疾病最终是致命的。在确定激动素是一种能够纠正 ELP1 剪接缺陷的小分子后，我们致力于对其进行优化，以生成可用于 FD 个体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，以开发一种用于 FD 的口服治疗方法，该方法可以有效地穿过血脑屏障并纠正神经系统中的 ELP1 剪接缺陷。我们证明，新型化合物 PTC258 可以有效地恢复小鼠组织（包括大脑）中的正确 ELP1 剪接，最重要的是，可以预防 FD 特有的进行性神经元变性。对表型小鼠模型 TgFD9；Elp1 进行的 PTC258 产后口服给药以剂量依赖性方式增加全长 ELP1 转录，并导致大脑中功能性 ELP1 增加 2 倍。值得注意的是，PTC258 治疗可改善表型 FD 小鼠的存活率、步态共济失调和视网膜变性。我们的研究结果强调了这种新型小分子类作为 FD 口服治疗的巨大治疗潜力。
