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年终盘点:2020年神经科学基因治疗和基因编辑十大研究突破

已有 781 次阅读 2021-1-11 10:41 |个人分类:神经科学临床和基础|系统分类:科研笔记

1. Nature medicine—基因治疗X连锁色素性视网膜炎初现曙光!!!牛津大学科学家发布了最新的临床试验结果

Abstract

Retinal gene therapy has shown greatpromise in treating retinitis pigmentosa (RP), a primary photoreceptordegeneration that leads to severe sight loss in young people. In the presentstudy, we report the first-in-human phase 1/2, dose-escalation clinical trialfor X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/:NCT03116113). The primary outcome of the study was safety, and secondaryoutcomes included visual acuity, microperimetry and central retinal thickness.Apart from steroid-responsive subretinal inflammation in patients at the higherdoses, there were no notable safety concerns after subretinal delivery of anadeno-associated viral vector encoding codon-optimized human RPGR(AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual fieldimprovements beginning at 1 month and maintained to the last point of follow-upwere observed in six patients.

参考文献:Initial results from a first-in-humangene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR.Nat Med. 2020 Mar;26(3):354-359.

 

2. Nature medicine—基因编辑治疗疾病初现曙光!!体细胞基因编辑可以改善猪和人iPSC的DMD模型的骨骼肌和心肌衰竭

Abstract

Frameshift mutations in the DMD gene,encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading toterminal muscle and heart failure in patients. Somatic gene editing bysequence-specific nucleases offers new options for restoring the DMD readingframe, resulting in expression of a shortened but largely functional dystrophinprotein. Here, we validated this approach in a pig model of DMD lacking exon 52of DMD (DMDΔ52), as well as in a corresponding patient-derived inducedpluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection ofadeno-associated viral vectors of serotype 9 carrying an intein-split Cas9(ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51(AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) andimproved skeletal muscle function. Moreover, systemic application ofAAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, includingdiaphragm and heart, prolonging survival and reducing arrhythmogenicvulnerability. Similarly, in induced pluripotent stem cell-derived myoblastsand cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excisionof exon 51 restored dystrophin expression and amelioreate skeletal myotubeformation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenicsusceptibility. The ability of Cas9-mediated exon excision to improve DMDpathology in these translational models paves the way for new treatmentapproaches in patients with this devastating disease.

参考文献:Somatic gene editing amelioratesskeletal and cardiac muscle failure in pig and human models of Duchennemuscular dystrophy. Nat Med. 2020 Feb;26(2):207-214.

 

3. Nature—帕金森病新突破!!将中脑星形胶质细胞转变为DA神经元可能治愈帕金森病(注意Fig.5e中的小错误)

Abstract

Parkinson's disease is characterizedby loss of dopamine neurons in the substantia nigra1. Similar to other majorneurodegenerative disorders, there are no disease-modifying treatments forParkinson's disease. While most treatment strategies aim to prevent neuronalloss or protect vulnerable neuronal circuits, a potential alternative is toreplace lost neurons to reconstruct disrupted circuits2. Here we report anefficient one-step conversion of isolated mouse and human astrocytes tofunctional neurons by depleting the RNA-binding protein PTB (also known asPTBP1). Applying this approach to the mouse brain, we demonstrate progressiveconversion of astrocytes to new neurons that innervate into and repopulateendogenous neural circuits. Astrocytes from different brain regions areconverted to different neuronal subtypes. Using a chemically induced model ofParkinson's disease in mouse, we show conversion of midbrain astrocytes todopaminergic neurons, which provide axons to reconstruct the nigrostriatalcircuit. Notably, re-innervation of striatum is accompanied by restoration ofdopamine levels and rescue of motor deficits. A similar reversal of disease phenotypeis also accomplished by converting astrocytes to neurons using antisenseoligonucleotides to transiently suppress PTB. These findings identify apotentially powerful and clinically feasible approach to treatingneurodegeneration by replacing lost neurons.

参考文献:Reversing a model of Parkinson'sdisease with in situ converted nigral neurons. Nature. 2020Jun;582(7813):550-556.

 

4.Nature—CRISPR-Cas9技术治疗天使人综合症!!通过CRISPR技术去沉默Ube3a可部分逆转天使人综合症的表型

Abstract

Angelman syndrome (AS) is a severeneurodevelopmental disorder caused by a mutation or deletion of the maternallyinherited UBE3A allele. In neurons, the paternally inherited UBE3A allele issilenced in cis by a long non-coding RNA called UBE3A-ATS. Here, as part of asystematic screen, we found that Cas9 can be used to activate ('unsilence')paternal Ube3a in cultured mouse and human neurons when targeted to Snord115genes, which are small nucleolar RNAs that are clustered in the 3' region ofUbe3a-ATS. A short Cas9 variant and guide RNA that target about 75 Snord115genes were packaged into an adeno-associated virus and administered to a mousemodel of AS during the embryonic and early postnatal stages, when thetherapeutic benefit of restoring Ube3a is predicted to be greatest1,2. Thisearly treatment unsilenced paternal Ube3a throughout the brain for at least 17months and rescued anatomical and behavioural phenotypes in AS mice. Genomicintegration of the adeno-associated virus vector into Cas9 target sites causedpremature termination of Ube3a-ATS at the vector-derived polyA cassette, orwhen integrated in the reverse orientation, by transcriptional collision withthe vector-derived Cas9 transcript. Our study shows that targeted genomicintegration of a gene therapy vector can restore the function of paternallyinherited UBE3A throughout life, providing a path towards a disease-modifyingtreatment for a syndromic neurodevelopmental disorder.

参考文献:Cas9 gene therapy for Angelmansyndrome traps Ube3a-ATS long non-coding RNA. Nature. 2020Nov;587(7833):281-284.

 

5.Science—你可以拥有近红外光视觉吗?人为表达近红外光感受器可以获得近红外视觉

Abstract

Enabling near-infrared lightsensitivity in a blind human retina may supplement or restore visual functionin patients with regional retinal degeneration. We induced near-infrared lightsensitivity using gold nanorods bound to temperature-sensitive engineeredtransient receptor potential (TRP) channels. We expressed mammalian or snakeTRP channels in light-insensitive retinal cones in a mouse model of retinaldegeneration. Near-infrared stimulation increased activity in cones, ganglioncell layer neurons, and cortical neurons, and enabled mice to perform a learnedlight-driven behavior. We tuned responses to different wavelengths, by usingnanorods of different lengths, and to different radiant powers, by usingengineered channels with different temperature thresholds. We targeted TRPchannels to human retinas, which allowed the postmortem activation of differentcell types by near-infrared light.

参考文献:Restoring light sensitivity usingtunable near-infrared sensors. Science. 2020 Jun 5;368(6495):1108-1113.

 

6. Nature medicine—新突破!!将CAR T细胞局部注射入脑脊液可以用于治疗髓母细胞瘤和室管膜瘤

Abstract

Recurrent medulloblastoma andependymoma are universally lethal, with no approved targeted therapies and fewcandidates presently under clinical evaluation. Nearly all recurrentmedulloblastomas and posterior fossa group A (PFA) ependymomas are locatedadjacent to and bathed by the cerebrospinal fluid, presenting an opportunityfor locoregional therapy, bypassing the blood-brain barrier. We identify threecell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed onmedulloblastomas and ependymomas, but not expressed in the normal developingbrain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13receptor α2 chimeric antigen receptor T cells as an effective treatment forprimary, metastatic and recurrent group 3 medulloblastoma and PFA ependymomaxenografts in mouse models. Finally, we demonstrate that administration ofthese chimeric antigen receptor T cells into the cerebrospinal fluid, alone orin combination with azacytidine, is a highly effective therapy for multiplemetastatic mouse models of group 3 medulloblastoma and PFA ependymoma, therebyproviding a rationale for clinical trials of these approaches in humans.

参考文献:Locoregional delivery of CAR T cellsto the cerebrospinal fluid for treatment of metastatic medulloblastoma andependymoma. Nat Med. 2020 May;26(5):720-731.

 

7. Nat Med—脊膜下输注shRNA-AAV可有效阻断ALS相关运动神经元变性

Abstract

Gene silencing with virally deliveredshRNA represents a promising approach for treatment of inheritedneurodegenerative disorders. In the present study we develop a subpialtechnique, which we show in adult animals successfully deliversadeno-associated virus (AAV) throughout the cervical, thoracic and lumbarspinal cord, as well as brain motor centers. One-time injection at cervical andlumbar levels just before disease onset in mice expressing a familialamyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-termsuppression of motoneuron disease, including near-complete preservation ofspinal α-motoneurons and muscle innervation. Treatment after disease onsetpotently blocks progression of disease and further α-motoneuron degeneration. Asingle subpial AAV9 injection in adult pigs or non-human primates using a newlydesigned device produces homogeneous delivery throughout the cervical spinalcord white and gray matter and brain motor centers. Thus, spinal subpialdelivery in adult animals is highly effective for AAV-mediated gene deliverythroughout the spinal cord and supraspinal motor centers.

参考文献:Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS. NatMed. 2020 Jan;26(1):118-130.

 

8. Cell stem cell—GDNF基因治疗可能显著提高干细胞移植治疗帕金森病的生物学效应

Abstract

Dopaminergic neurons (DAns),generated from human pluripotent stem cells (hPSCs), are capable of functionallyintegrating following transplantation and have recently advanced to clinicaltrials for Parkinson's disease (PD). However, pre-clinical studies havehighlighted the low proportion of DAns within hPSC-derived grafts and theirinferior plasticity compared to fetal tissue. Here, we examined whetherdelivery of a developmentally critical protein, glial cell line-derivedneurotrophic factor (GDNF), could improve graft outcomes. We tracked theresponse of DAns implanted into either a GDNF-rich environment or after a delayin exposure. Early GDNF promoted survival and plasticity of non-DAns, leadingto enhanced motor recovery in PD rats. Delayed exposure to GDNF promotedfunctional recovery through increases in DAn specification, DAn plasticity, andDA metabolism. Transcriptional profiling revealed a role for mitogen-activatedprotein kinase (MAPK)-signaling downstream of GDNF. Collectively, these resultsdemonstrate the potential of neurotrophic gene therapy strategies to improvehPSC graft outcomes.

参考文献:Viral Delivery of GDNF PromotesFunctional Integration of Human Stem Cell Grafts in Parkinson's Disease. CellStem Cell. 2020 Apr 2;26(4):511-526.e5.

 

9. Nature methods—科学家研发可静脉注射且特异靶向于不同脑细胞类型的AAVs

Abstract

Recombinant adeno-associated viruses(rAAVs) are efficient gene delivery vectors via intravenous delivery; however,natural serotypes display a finite set of tropisms. To expand their utility, weevolved AAV capsids to efficiently transduce specific cell types in adult mousebrains. Building upon our Cre-recombination-based AAV targeted evolution(CREATE) platform, we developed Multiplexed-CREATE (M-CREATE) to identifyvariants of interest in a given selection landscape through multiple positiveand negative selection criteria. M-CREATE incorporates next-generationsequencing, synthetic library generation and a dedicated analysis pipeline. Wehave identified capsid variants that can transduce the central nervous systembroadly, exhibit bias toward vascular cells and astrocytes, target neurons withgreater specificity or cross the blood-brain barrier across diverse murinestrains. Collectively, the M-CREATE methodology accelerates the discovery ofcapsids for use in neuroscience and gene-therapy applications.

参考文献:Multiplexed Cre-dependent selectionyields systemic AAVs for targeting distinct brain cell types. Nat Methods. 2020May;17(5):541-550.

 

10. Cell—重磅!!使用CRISPR-CasRx技术将胶质细胞转变为神经元可以显著修复由大脑疾病引起的神经损伤和神经变性

Abstract

Conversion of glial cells intofunctional neurons represents a potential therapeutic approach for replenishingneuronal loss associated with neurodegenerative diseases and brain injury.Previous attempts in this area using expression of transcription factors werehindered by the low conversion efficiency and failure of generating desiredneuronal types in vivo. Here, we report that downregulation of a singleRNA-binding protein, polypyrimidine tract-binding protein 1 (Ptbp1), using invivo viral delivery of a recently developed RNA-targeting CRISPR system CasRx, resultedin the conversion of Müller glia into retinal ganglion cells (RGCs) with a highefficiency, leading to the alleviation of disease symptoms associated with RGCloss. Furthermore, this approach also induced neurons with dopaminergicfeatures in the striatum and alleviated motor defects in a Parkinson's diseasemouse model. Thus, glia-to-neuron conversion by CasRx-mediated Ptbp1 knockdownrepresents a promising in vivo genetic approach for treating a variety ofdisorders due to neuronal loss.

参考文献:Glia-to-Neuron Conversion byCRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice. Cell. 2020Apr 30;181(3):590-603.e16.

 

 

语音解读(具体见链接)


2020年十大研究进展名录

1. 年终盘点:2020年阿尔茨海默病十大研究突破(附语音解读)
2. 盘点2020年AD十大临床研究突破:聚焦外周诊断标志物、p-tau和临床前期预防
3. 年终盘点:2020年帕金森病十大基础研究突破(附语音解读)
4. 年终盘点:2020年帕金森病十大临床研究突破
5. 年终盘点:2020年神经科学30项基础研究突破(附解读链接)
6. 年终盘点:2020年ALS/FTD十大研究突破(附语音解读)
7. 年终盘点:2020年神经病学领域25项临床研究突破(附解读链接)
8. 年终盘点:2020年脑血管领域十大基础研究突破
9. 年终盘点:2020年神经免疫和炎症十大研究突破
10. 年终盘点:2020年脑-肠-微生物轴十大研究突破
11. 年终盘点:2020年神经系统衰老及衰老的分子细胞机制十大研究突破
12. 年终盘点:2020年痛觉基础和临床十大研究突破
13. 年终盘点:2020年睡眠和生物节律领域十大研究突破
14. 年终盘点:2020年抑郁症十大研究突破


2019年十大研究进展名录

1. 年终盘点:2019年帕金森病十大基础研究进展

2. 年终盘点:2019年帕金森病十大临床研究进展

3. 年终盘点:2019年阿尔茨海默病十大基础研究进展

4. 年终盘点:2019年阿尔茨海默病十大临床研究进展

5. 年终盘点:2019年神经科学领域十大基础研究进展

6. 年终盘点:2019年抑郁症领域十大基础研究进展(一半来自中国)

7. 年终盘点:2019年脑血管病领域十大基础研究进展

8. 年终盘点:2019年神经炎症领域十大基础研究进展

9. 年终盘点:2019年神经活动记录十大基础研究进展

10. 年终盘点:2019年ALS/FTD十大基础研究进展

11. 年终盘点:2019年医学和生物学领域深度学习和神经网络十大基础研究进展

12. 年终盘点:2019年神经内科十大临床研究突破

13. 年终盘点:2019年疼痛防治和痛觉机制十大研究突破

14. 年终盘点:2019年睡眠和失眠领域十大研究突破

15.年终盘点:2019年神经发育及成年神经再生十大研究突破

16. 年终盘点:2019年大脑学习和记忆的十大研究突破

17. 年终盘点:2019年衰老和长寿十大研究突破

18. 年终盘点:2019年自闭症十大研究突破


2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症(ALS)十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破




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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究:意识的本质、组成、运行机制及其物质载体;不同意识层次的操控和干预,意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控:记忆的形成和消退机制,记忆的人为移植和记忆的人为消除等;

3. 痴呆研究:阿尔茨海默病的机制和治疗研究,血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究:喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究:性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究,包括脑卒中、脊髓损伤机制研究,神经干细胞移植研究,新型神经修复技术,神经康复技术。

13. 精神类疾病的机制和干预研究:自闭症、精分、抑郁症、智能障碍、药物成瘾等;

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究,包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术:光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究,包括脑机接口、神经刺激芯片、记忆存储芯片,意识存储芯片,人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术:包括任何机械肢体的人类移植,大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术:高分辨率成像技术、大型电极微阵列技术等。


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专门解析最新的临床指南和循证医学证据 

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专门解析最新的神经科学基础和临床研究进展 

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