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Science子刊︱前沿!基因疗法通过重组大脑功能连接以改善帕金森病症状

LTNeurosci 逻辑神经科学 2019-06-30

Authorship (Chinese)︱LTNeurosci

Responding Editor︱LTNeurosci

Deaths from Parkinson disease per million persons in 2012 0–1    2–4   5–6    7–8    9–10    11–12    13–17    18–36    37–62    63–109https://en.wikipedia.org/wiki/Parkinson%27s_disease

到目前为止,尽管在神经退行性疾病的治疗方面已经取得了重大进展,但是这些治疗往往是针对某些特定症状的,也没有实质性地改变(modify)疾病的潜在进展【1】

比如,在帕金森病(PD)中,使用左旋多巴(levodopa )等多巴胺能药物(dopaminergic drugs)可以替代PD患者脑内缺少的多巴胺,从而可以在数年之内有效延缓PD临床症状;然而,近年来,有学者认为左旋多巴可通过引起黑质多巴胺能神经元的变性而致使疾病进一步恶化 【2】。随着此类药物使用时间的延长,药性会逐渐减弱,并且会逐渐暴露出异动症及精神错乱等诸多不良反应【3】。此外,长期使用左旋多巴会引起同型半胱氨酸升高,而同型半胱氨酸增高可诱发认知缺损及痴呆【4】。PD患者中PD性痴呆的发生率可高达4%-93% 【5】

然而,随着腺相关病毒(adeno-associated virus,AAV)载体的出现,极大鼓励了研究者不断探索中枢神经系统中的基因治疗(gene therapy),并期待基因治疗能成为PD的替代疗法【6-7】

在PD中,神经退化始于黑质致密部多巴胺能神经元的丧失,继而触发一系列复杂的下游变化【8】实际上当表现出临床症状时大脑的功能连接和新陈代谢已经发生了大范围的改变【9】丘脑底核(subthalamic nucleus,STN)的过度激活便是这些下游变化的表现之一,而STN又在运动回路中起着关键的调控作用【10】

研究已经证明STN是PD手术干预的成功靶点,即深部脑刺激(deep brain stimulation)和损伤(lesioning),因此被认为是基因治疗的一个良好候选靶点【11】

谷氨酸脱羧酶(glutamic acid decarboxylase,GAD)是将谷氨酸经脱羧而转化成抑制性神经递质γ氨基丁酸(GABA)及二氧化碳的限速酶【12】而GABA作为一种抑制性神经递质,可调控GABA能神经元中动作电位的传导【12】。GABA按用途可以分为两类:一类作为抑制性神经递质参与动作电位传导;另一类则参与代谢【12】。GABA系统的紊乱与一系列神经系统的疾病例如癫痫、焦虑障碍、僵人综合征、精神分裂症和PD等有密切联系【13】

基因传递的选择依赖于基因位点的选取。通过谷氨酸脱羧酶基因GAD的局部转移部分STN神经元可以被转化为抑制性表型降低STN的过度激活从而缓解PD运动症状【6, 11】

PD患者单侧STN AAV2-GAD给药的第I期临床试验表现出可喜的结果,随后的第II期临床试验(the blinded, sham-controlled phase 2 trial)进一步表明:接受双侧STN AAV2-GAD治疗的患者有了明显的功能性改善,时长为1年【7, 14】

然而,这种功能性改善背后的确切机制仍然不清楚。为了充分了解STN AAV2-GAD治疗的效果,来自(美国)范斯坦医学研究所(The Feinstein Institute for Medical Research)(美国)宾夕法尼亚大学佩雷尔曼医学院、及(美国)威尔康奈尔医学院的合作团队通过采用代谢网络分析技术(metabolic network analysis),成果揭示出:GAD基因治疗的效果是通过脑代谢而进行调节的;代谢网络分析可以对神经系统疾病的治疗效果进行有效评估【15】。该项前沿性成果已于2018年11月28日以Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity为题发表在Science Translational Medicine(IF=16.710)【15】

在之前的研究中,David Eidelberg(本文通讯作者)等人已经证明:作为一种疾病特异性代谢网络,PD相关协方差模式(the PD–related covariance pattern,PDRP)是一种客观性的敏感性的、且与PD患者运动评定相关联的疾病进展指标【9, 16】。此外,他们还发现,急性左旋多巴输注或STN深脑刺激能够迅速抑制PDRP的表达,且其比例与患者运动性改善成正比【16-17】

因此,在这项研究中,Martin Niethammer(本文第一作者)等人旨在确定:是否AAV2-GAD基因治疗像传统疗法一样能够调节PDRP活性?又或者其以不同的网络发挥作用?以及慰剂反应的临床改善程度

首先,研究者们从第II期临床试验中,重点分析了16名接受基因治疗PD患者(received STN AAV2-GAD gene therapy )和21名随机接受假手术治疗的PD患者(randomized to sham surgery(bilateral burr holes and pump placement)) FDG PET成像数据。这些患者都进行了术前、术后6个月和术后12个月的代谢FDG PET扫描 (Fig.1-2)

Fig. 1  AAV2-GAD–treated subjects exhibit a treatment-related metabolic brain network

结果表明:接受GAD基因治疗的PD患者形成了一种独特的依赖治疗的多突触脑回路,被命名为GAD基因关联模式GAD–related pattern,简称GADRP(Fig.1-2) (Table 1-2)。而GADRP反映了连接STN和运动皮层区域的新的多突触功能通路的形成(Fig.1)

Fig. 2  STN AAV2-GAD gives rise to new functional connections between GADRP network nodes.

其次,治疗组和假手术组的患者在对其接受的治疗均不知情的情况下,都表现出假手术关联模式(the sham surgery–related pattern,简称 SSRP)(Fig.3)SSRP是一种之前鉴定的新的安慰剂网络(placebo network)【18-19】

Fig. 3  GADRP expression is unaffected by unblinding.

然而,在接受STN AAV2-GAD基因治疗的受试者中只有GAD基因关联模式的出现与临床症状改善有关(Fig.4)

因此,文章总的来说,治疗诱导性脑回路(treatment-induced brain circuits )可用于临床试验中分离真正的治疗反应并为我们深入了解PD潜在的生物学机制提供了机会

Fig. 4 GAD therapy improves clinical symptoms without suppressing PDRP expression.

此外,令人振奋的信息是,2018年10月9日,基因疗法公司MeiraGTx(a vertically integrated, clinical stage gene therapy company)宣布其已通过全股票交易收购Vector Neurosciences公司【20】

MeiraGTx公司旨在:通过此次收购,将扩大其临床阶段候选产品,包括编码GAD的AAV-GAD用于PD的治疗。目前,AAV-GAD已完成第II期的临床试验是首个成功进行随机、双盲对照试验的用于脑部疾病的基因疗法候选产品【20】

AAV-GAD是一款正在研发中的基因疗法药物,其能将GAD基因递送至STN,从而增加人脑中的主要抑制性神经递质,即GABA的生成。GAD是GABA合成中的限速酶,因此,通过基因疗法增加STN中GAD的表达,可以使得PD患者运动回路正常化,最终改善PD症状,同时,不会对其他可能造成现有疗法并发症的大脑区域造成影响。而且,AAV-GAD已获得美国FDA的快速通道资格【20】

补充阅读

【1】Lancet Neurology 综述︱前沿!大脑淋巴通路在神经功能障碍(/疾病)中的清除机制的研究进展

【2】Science︱重磅!抑制PARPA-1激活可阻止帕金森病中多巴胺能神经元退化的新机制的阐明

【3】Nature Neuroscience焦点︱神经退行性疾病的最新研究进展

【4】Nature Communications:LRRK2激酶调控α-核突触蛋白的积累,可作为治疗帕金森的药物靶标

【5】Nature:前沿!Parkin/PINK1可缓解由STING诱发的炎症,线粒体自噬新模型或可挽救PD

通讯作者 Dr. David Eidelberg 简介

David Eidelberg, MD

Professor & Head, Feinstein Center for Neurosciences, The Feinstein Institute for Medical Research

Professor of Molecular Medicine and Neurology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Email: david1@northwell.edu

About the Investigator

David Eidelberg, MD is internationally recognized for his pioneering work using functional brain networks as biomarkers of neurological disease. Using functional brain imaging, he and his research group have identified and characterized network biomarkers for degenerative brain disorders such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and frontotemporal dementia, as well as dystonia, tic disorder, and tremor. His work has led to validated network-based algorithms to aid in the diagnosis and management of patients with these disorders.

Dr. Eidelberg received his medical degree from Harvard Medical School. After completing residency training in neurology at Harvard, he pursued postdoctoral training in brain imaging with MRI (at The National Hospital, London UK) and PET (at Cornell in New York USA). He has led the Center for Neurosciences at The Feinstein Institute for Medical Research since its founding in 2001, serving as Director and Susan and Leonard Feinstein Professor of Neurology and Neuroscience. Dr. Eidelberg has received many grants and awards for his work from prominent research agencies including NIH and the Michael J. Fox Foundation. He is the author of over 350 peer-reviewed research articles, editorials, and reviews, as well as a textbook (Brain Imaging in Parkinson’s Disease, Oxford University Press 2011). Dr. Eidelberg serves on the editorial boards of several high-impact journals. He is a scientific advisor to the Michael J. Fox Foundation, the U.S. Department of Defense, and the COBRE Center for Neurodegeneration and Translational Neuroscience (CNTN).

Research focus

Dr. Eidelberg directs a leading imaging research program in brain disease. His program is internationally recognized for developing novel imaging techniques to characterize and quantify neural circuits in neurodegenerative disorders and to study their modulation by using functional imaging with PET and fMRI.

文献参考

【1】J. A. Obeso, et al., Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov. Disord. 32, 1264–1310 (2017).

【2】Wu N, et al., NMDA receptor regulation of levodopa-induced behavior and changes in striatal G protein-coupled receptor kinase 6 and β-arrestin-1 expression in parkinsonian rats. Clin Interv Aging. 8:347-352 (2013).

【3】Muller T. Catechol-O-methyltransferase enzyme: cofactor S-adenosyl-L-methionine and related mechanisms. Int Rev Neurobiol.95:49-71 (2010).

【4】Hooshmand B, et al., Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med. 271(2):204-212 (2012).

【5】Jellinger KA. Neurobiology of cognitive impairment in Parkinson's disease. Expert Rev Neurother.12: 1451-1466 (2012).

【6】J. Luo, M. G. et al., Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science 298, 425–429 (2002).

【7】P. A. LeWitt, et al., AAV2-GAD gene therapy for advanced Parkinson's disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–319 (2011).

【8】W. Poewe, et al., Parkinson disease. Nat. Rev. Dis. Primers 3, 17013 (2017).

【9】K. A. Schindlbeck, et al., Network imaging biomarkers: Insights and clinical applications in Parkinson's disease. Lancet Neurol. 17, 629–640 (2018).

【10】M. D. Bevan, et al., Cellular principles underlying normal and pathological activity in the subthalamic nucleus. Curr. Opin. Neurobiol. 16, 621–628 (2006).

【11】M. G. Kaplitt, M. J. During, GAD gene therapy for Parkinson’s disease, in Translational Neurosicence - Fundamental Approaches for Neurological Disorders, M. H. Tuszynski, Ed. (Springer Science+Business Media, 2016), chap. 5, pp. 89–98.

【12】杜昭, 等. 谷氨酸脱羧酶在神经系统及雄性生殖系统中的功能 [J].生命的化学, 2013, 33(2): 96-100.

【13】Wong CG, Bottiglieri T, Snead OC 3rd. GABA, γ- hydroxybutyric acid, and neurological disease. Ann Neurol. 54: S3-S12(2003).

【14】M. G. Kaplitt, et al., Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: An open label, phase I trial. Lancet 369, 2097–2105 (2007).

【15】Niethammer et al., Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity. Sci. Transl. Med. 10, eaau0713 (2018)

【16】M. Niethammer, D. Eidelberg, Metabolic brain networks in translational neurology: Concepts and applications. Ann. Neurol. 72, 635–647 (2012).

【17】A. Vo, et al., Parkinson's disease-related network topographies characterized with resting state functional MRI. Hum. Brain Mapp. 38, 617–630 (2017).

【18】F. Benedetti, et al., Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J. Physiol. 587, 3869–3883 (2009).

【19】C. G. Goetz, et al., Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions. Mov. Disord. 23, 690–699 (2008).

【20】http://investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-acquisition-vector-neurosciences-gains-phase


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