NEJM发布基因治疗重大捷报!
生物通 · 2016/05/04
来自牛津大学的一项研究报告称,开创性的基因治疗使得罹患一种罕见形式遗传性失明的患者在长达4年的时间里恢复了部分的视力,这为利用基因疗法来治疗一些视力丧失的常见原因带来了希望。


来自牛津大学的一项研究报告称,开创性的基因治疗使得罹患一种罕见形式遗传性失明的患者在长达4年的时间里恢复了部分的视力,这为利用基因疗法来治疗一些视力丧失的常见原因带来了希望。

这一技术涉及到将一种病毒注入到眼睛中为无脉络膜症患者递送数十亿的健康基因以替代一个重要的缺失基因,它在长达4年的时间里持续地改善了一些患者的视力。

无脉络膜症的发病率为1/50,000。由于脉络膜、视网膜色素上皮细胞和视网膜的退化,这种疾病能够引起视力的逐渐丧失。对于无脉络膜症,还没有很好的治疗方法,最终感光细胞也会退化,从而导致中年期的完全失明。

新研究提供了迄今为止最强有力的证据证明,在人类中基因治疗的效应有可能是永久性的,因此可以通过单次治疗来治愈许多类型的遗传性失明。其中包括累及年轻人的视网膜色素变性,和影响老年人的老年性黄斑变性。

研究结果报告在4月27日《新英格兰医学》(NEJM)杂志上,来自牛津大学的医生检测了6名患者在牛津大学ohnRadcliffe医院接受基因治疗后4年的视力状况。这6名患者是世界上首批在由卫生署和维康基金会资助的一项试验中接受这一无脉络膜症治疗程序的人。

这一基因治疗的目的在于减慢或阻止视力丧失,然而两名患者的视力获得了显著改善,且这一效应持续了至少4年时间,在这一期间他们未接受治疗的眼睛视力下降了。另外3人在此期间接受治疗的眼睛维持了视力。第6名接受较低剂量治疗的患者双眼视力缓慢下降。

人们希望理想的情况下患者将在疾病进展的早期接受基因治疗以阻止视力丧失,因为这种治疗预计是长期持久的。无脉络膜症的患者视网膜中缺失了一个关键的基因,这一技术涉及到注入一种病毒传送数十亿的健康基因以替代这一缺失基因。

这项研究的主要研究者RobertMacLaren教授说:“近期有人对基因治疗的长期疗效提出质疑,但现在我们获得了明确的证据证明,单次注射病毒载体后这些效应是持久性的。甚至提高一点点中心视力也可以给予这些患者相当大的独立性。”

“基因治疗是一种具有很大潜力的医学新技术。随着我们对遗传学认识的不断深入,我们意识到在疾病发病之前纠正错误基因有可能是最有效的治疗。基因治疗利用了病毒的感染特性将DNA插入到细胞中,不过其除去了病毒DNA,用实验室中重编程的DNA来替代了它,以纠正患者体内的错误基因。”

“在这一案例中,能够成功地让治疗效应维持至少几年,是因为病毒DNA获得了最佳的设计,采用先进的手术技术将病毒载体传送到了正确的位置。总之,这是我们一直在等待的突破。”

维康基金会创新主任StephenCaddick补充说:“永久地恢复遗传性失明患者的视力将是一个非凡的医学成就。这是我们第一次看到仅接受一轮治疗后视力的永久改变。这是朝着基因治疗成为这些患者常规治疗组成部分这一时代迈出的真正的一步。”

一项发布2016年4月ScienceTranslationalMedicine杂志上的研究报告了一则好消息,在采用圣犹大儿童研究医院和美国国家过敏和传染病研究所(NIAID)开发的新型基因疗法治疗后,罹患一种严重遗传性免疫缺陷病的青少年和年轻成人病情得到了改善。这项研究涉及了罹患严重联合免疫缺陷病(SCID-X1),也称作为气泡男孩症("BubbleBoy"disease)的五名男性,他们均在NIAID接受了治疗。

不过,近期西雅图生物技术公司BioViva的一项抗衰老基因治疗也引发了争议。去年,BioViva的首席执行官ElizabethParrish搭乘飞机奔赴哥伦比亚,在那里她通过多次注射,接受了她公司开发的两种实验性基因疗法。一种疗法旨在延长染色体的末端(称为端粒),而另一种疗法则旨在增加肌肉质量。4月22日在其网站上,BioViva报道了Parrish第一个治疗的结果:她的白细胞的端粒变得更长,从2015年9月的6.71kb到2016年3月的7.33kb。

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  • Visual Acuity after Retinal Gene Therapy for Choroideremia

    Two recent clinical reports of retinal gene therapy with adeno-associated virus (AAV) vectors in patients with Leber’s congenital amaurosis showed initial gains in visual function that subsequently declined.1,2 We previously reported early improvement in visual acuity in two of six patients who received retinal gene therapy in one eye (the study eye) to treat choroideremia,3 a disease that is characterized by atrophy of the choriocapillaris and retinal pigment epithelium and involves vision loss that leads to blindness. Choroideremia is caused by loss-of-function mutations in the gene CHM. We delivered nonmutated CHM in an AAV vector (AAV.REP1) by subfoveal injection into the vicinity of the retinal pigment epithelium and photoreceptor cells, the dysfunction of which is presumed to be a contributing factor in vision loss. Here we report that the early improvement that we observed in two of the six patients was sustained at 3.5 years after treatment, despite progressive degeneration in the other eyes (the control eyes). The control eyes did not receive the intervention, and visual acuity in the control eyes was better than the visual acuity in the study eyes at baseline. The best corrected visual acuity was reported as the number of letters correctly read by the patient on an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart at 4 m. Two patients (Patients 1 and 4) had advanced disease, and the visual acuity in the study eyes at baseline in these patients was several lines below normal (each line contains 5 letters) on the ETDRS chart (Table 1TABLE 1 Visual Acuity in Patients with Choroideremia Who Received Retinal Gene Therapy. ). By 3.5 years, visual acuity in the treated study eye had increased by 21 letters (>4 lines) from baseline on the ETDRS chart in Patient 1 and by 18 letters (>3 lines) in Patient 4. In contrast, over the same period, visual acuity in the control eyes decreased by 18 letters in Patient 1 and by 6 letters in Patient 4. A cataract developed in the study eye in Patient 4 at 2 years. This cataract was subsequently removed, but the removal was not the primary reason for the gain in visual acuity recorded at 3.5 years. The visual acuity at 3.5 years was similar to the level recorded 12 months after surgery, before the cataract was clinically significant. The other four patients had good visual acuity at baseline and therefore a limited scope for improvement. Patient 3, the youngest patient, had the largest area of surviving retina and the best pretreatment visual acuity — 20/16 (89 ETDRS letters). This visual acuity returned to the baseline level 12 months after the administration of gene therapy and was sustained until the last follow-up. No loss of visual acuity was observed in the untreated control eye during this time, probably because the disease was still in the early stages. However, the treated eye of Patient 3 did show improvement on an electrophysiological study. This test measures a global macular response and may therefore be more relevant in younger patients with larger areas of surviving retina (Fig. S3 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The levels of visual acuity in the study eyes in Patients 2, 5, and 6 all returned to baseline levels by 6 months after treatment, but by the 3.5-year follow-up, the visual acuity of the study and control eyes in Patient 6 had declined by 29 and 18 letters, respectively. Patient 6 received a lower total vector dose than the other patients in the trial; we speculate that the loss of visual acuity in this patient was caused by progressive degeneration of cells in the fovea rather than a toxic effect of the vector. In contrast, at the 3.5-year follow-up, the visual acuity in the injected eyes in Patients 2 and 5 remained close to that at baseline, whereas the visual acuity of the control eye was lower by 10 and 11 letters, respectively. Best corrected visual acuity is a reliable marker of visual function. In contrast to Leber’s congenital amaurosis, in which visual acuity is generally profoundly affected early in life, choroideremia and most types of retinitis pigmentosa are characterized by progressive loss of the visual field, with visual acuity remaining close to normal levels until the very late stages of disease. Therefore, in some patients, the effect of preserving visual acuity with the use of retinal gene therapy may take several years to become apparent.

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