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Adeno-associated virus as a delivery vector for gene therapy of human diseases

Signal Transduction and Targeted therapy 2024年第5期9卷 1808-1840页

作者： Jiang-Hui Wang Dominic J.Gessler Wei Zhan Thomas L.Gallagher Guangping Gao Horae Gene therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia department of neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA department of neurosurgery University of MinnesotaMinneapolisMN55455USA department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

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Assessing donor-recipient arterial pressure dynamics in STA-MCA bypass for moyamoya disease

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中华神经外科杂志(英文) 2024年第3期10卷 1-10页

作者： Helmy Mohamed Liao Yujun Zhao Zehao Li Zhiqi He Kangmin Xu Bin neurosurgery department Fudan University Huashan Hospital Shanghai People’s Republic of China National Center for neurological Disorders Shanghai People’s Republic of China

Background In bypass surgery for moyamoya disease (MMD), the superficial temporal artery’s (STA) pressure needs to surpass that of the cortical M4 recipient of the middle cerebral artery (MCA), boosting cerebral blood flow into the MCA and enhancing cerebral circulation. This study investigates the STA-MCA arterial pressure parameters and gradients during bypass surgery, aiming to deepen our understanding of hemodynamic shifts pre- and *** DSA imaging data were prospectively collected from patients diagnosed with bilateral MMD who underwent STA-MCA bypass surgery between 2022 and 2023 and stratified according to the Suzuki stage. The mean arterial pressure (MAP) of the donor and recipient arteries was directly measured during the STA-MCA bypass procedure, and these data were statistically analyzed and *** Among 48 MMD patients, Suzuki grading revealed that 43.8% were in early stages (II and III), while 56.2% were in advanced stages (IV, V, and VI). Predominantly, 77.1% presented with ischemic-type MMD and 22.9% with hemorrhagic type. Pre-bypass assessments showed that 62.5% exhibited antegrade blood flow direction, and 37.5% had retrograde. The mean recipient artery pressure was 35.0 ± 2.3 mmHg, with a mean donor-recipient pressure gradient (δP) of 46.4 ± 2.5 mmHg between donor and recipient arteries. Post-bypass, mean recipient artery pressure increased to 73.3 ± 1.6 mmHg. No significant correlation (r= 0.18,P= 0.21) was noted between δP and Suzuki *** Our study elucidated that cerebral blood pressure significantly decreases beyond the moyamoya network at the distal M4 segment. Furthermore, we observed bidirectional flow in MCA territories and a significant positive pressure gradient between the STA and M4 segments. The lack of correlation between Suzuki stages and M4 pressures indicates that angiographic severity may not reflect hemodynamic conditions before surgery, highlighting the need for customized surgical appr

关键词： Moyamoya disease Pressure gradient Cerebral hemodynamic Suzuki stage

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Safety and efficiency of Wharton’s Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury:First results of a phase I study

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World Journal of Stem Cells 2024年第6期16卷 641-655页

作者： Serdar Kabatas ErdinçCivelek Osman Boyalı Gülseli Berivan Sezen Omer Ozdemir Yeliz Bahar-Ozdemir Necati Kaplan Eyüp Can Savrunlu Erdal Karaöz department of neurosurgery University of Health Sciences TurkeyGaziosmanpaşa Training and Research HospitalIstanbul 34360Türkiye Center for Stem Cell&Gene therapy Research and Practice University of Health Sciences TurkeyIstanbul 34255Türkiye department of neurosurgery University of Health SciencesGaziosmanpaşa Training and Research HospitalIstanbul 34255Türkiye department of Physical Medicine and Rehabilitation Health Sciences University Sultan Abdulhamid Han Training and Research HospitalIstanbul 34668Türkiye department of neurosurgery Istanbul Rumeli UniversityÇorlu Reyap HospitalTekirdağ59860Türkiye department of neurosurgery Nevşehir State HospitalNevşehir 50300Türkiye Center for Regenerative Medicine and Stem Cell Research&Manufacturing(LivMedCell) Liv HospitalIstanbul 34340Türkiye department of Histology and Embryology Istinye UniversityFaculty of MedicineIstanbul 34010Türkiye Center for Stem Cell and Tissue Engineering Research and Practice Istinye UniversityIstanbul 34340Türkiye

BACKGROUND Traumatic brain injury(TBI)is characterized by a disruption in the normal function of the brain due to an injury following a trauma,which can potentially cause severe physical,cognitive,and emotional *** cell transplantation has evolved as a novel treatment modality in the management of TBI,as it has the potential to arrest the degeneration and promote regeneration of new cells in the ***’s Jelly-derived mesenchymal stem cells(WJ-MSCs)have recently shown beneficial effects in the functional recovery of neurological *** To evaluate the safety and efficiency of MSC therapy in *** We present 6 patients,4 male and 2 female aged between 21 and 27 years who suffered a *** 6 patients underwent 6 doses of intrathecal,intramuscular(i.m.)and intravenous transplantation of WJ-MSCs at a target dose of 1×106/kg for each application *** was assessed using the Modified Ashworth scale(MAS),motor function according to the Medical Research Council Muscle Strength Scale,quality of life was assessed by the Functional Independence Measure(FIM)scale and Karnofsky Performance Status *** Our patients showed only early,transient complications,such as subfebrile fever,mild headache,and muscle pain due to ***,which resolved within 24 *** the one year follow-up,no other safety issues or adverse events were *** 6 patients showed improvements in their cognitive abilities,muscle spasticity,muscle strength,performance scores and fine motor skills when compared before and after the *** values,which we used to assess spasticity,were observed to statistically significantly decrease for both left and right sides(P<0.001).The FIM scale includes both motor scores(P<0.05)and cognitive scores(P<0.001)and showed a significant increase in pretest posttest *** difference observed in the participants’Karnofsky Performance Scale values pre and post the intervention was statistically si

关键词： Traumatic brain injury Wharton Jelly Stem cell therapy Transplantation Mesenchymal stem cell

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Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration

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Neural Regeneration Research 2024年第1期19卷 49-54页

作者： Ye Xiong Asim Mahmood Michael Chopp department of neurosurgery Henry Ford HospitalDetroitMIUSA department of Neurology Henry Ford HospitalDetroitMIUSA department of Physics Oakland UniversityRochesterMIUSA

Traumatic brain injury is a serious and complex neurological condition that affects millions of people *** significant advancements in the field of medicine,effective treatments for traumatic brain injury remain ***,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain *** vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and *** administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional *** preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor *** further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain *** this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.

关键词： biomarkers extracellular vesicles functional outcome mesenchymal stem/stromal cells neuroinflammation neuroplasticity neuroprotection traumatic brain injury

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Direct Ischemic Postconditioning Following Stroke Thrombectomy:A Promising therapy for Reperfusion Injury

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Neuroscience Bulletin 2024年第7期40卷 1017-1020页

作者： Jing Wang Lu Yang Longfei Wu Sijie Li Changhong Ren Yuchuan Ding Ming Wei Xunming Ji Wenbo Zhao department of Neurology Xuanwu HospitalCapital Medical UniversityBeijing 100053China department of Emergency Xuanwu HospitalCapital Medical UniversityBeijing 100053China Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine Xuanwu HospitalCapital Medical UniversityBeijing 100053China department of neurosurgery Wayne State University School of MedicineDetroitMI48201USA Beijing Institute for Brain Disorders Capital Medical UniversityBeijing 100069China department of neurosurgery Tianjin Huanhu HospitalTianjin 300222China department of neurosurgery Xuanwu HospitalCapital Medical UniversityBeijing 100053China

Recanalization of occluded vessels and timely reperfusion are the primary therapies for acute ischemic stroke(AIS),with endovascular thrombectomy proven as the most effective therapy for large-vessel recanalization and improved outcomes of AIS ***,despite a high recanalization rate of 90% or even higher,the rate of 3-month functional independence is approximately 50%,while mortality remains around 15%[1].

关键词： mortality acute therapy

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endovascular treatment of ruptured lobulated anterior communicating artery aneurysms:A retrospective study of 24 patients

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World Journal of Clinical Cases 2024年第15期12卷 2529-2541页

作者： Sheng-Xuan Huang Xun-Ping Ai Ze-Hui Kang Zhi-Yong Chen Ren-Man Li Zu-Chao Wu Feng Zhu department of neurosurgery Sanming First Hospital Affiliated to Fujian Medical UniversitySanming 365000Fujian ProvinceChina

BACKGROUND Lobulated intracranial aneurysm is a special type of aneurysm with at least one additional cyst in the neck or body of the *** intracranial aneurysm is a complex aneurysm with complex morphology and structure and weak tumor wall,which is an independent risk factor for rupture and *** aneurysms located in the anterior communicating artery complex account for 36.9%of all intracranial lobular *** to its special anatomical structure,both craniotomy and endovascular treatment are more *** with single-capsule aneurysms,craniotomy for lobular intracranial aneurysms has a higher risk and complication *** To investigate the efficacy and safety of endovascular treatment for ruptured lobulated anterior communicating artery aneurysm(ACoAA).METHODS Patients with ruptured lobulated ACoAA received endovascular treatment in Sanming First Hospital Affiliated to Fujian Medical University from June 2020 to June 2022 were retrospectively *** demographic,clinical and imaging characteristics,endovascular treatment methods and follow-up results were *** A total of 24 patients with ruptured lobulated ACoAA were included,including 9 males(37.5%)and 15 females(62.5%).Their age was 56.2±8.9 years old(range 39-74).The time from rupture to endovascular treatment was 10.9±12.5 *** maximum diameter of the aneurysms was 5.1±1.0 mm and neck width were 3.0±0.7 *** patients(79.2%)were double-lobed and 5(20.8%)were ***'s grade:Grade 2 in 16 cases(66.7%),grade 3 in 6 cases(25%),and grade 4 in 2 cases(8.3%).Hunt-Hess grade:Grade 0-2 in 5 cases(20.8%),grade 3-5 in 19 cases(79.2%).Glasgow Coma Scale score:9-12 in 14 cases(58.3%),13-15 in 10 cases(41.7%).Immediately postprocedural Raymond-Roy grade:grade 1 in 23 cases(95.8%),grade 2 in 1 case(4.2%).Raymond-Roy grade in imaging follow-up for 2 wk to 3 months:grade 1 in 23 cases(95.8%),grade 2 in 1 case(4.2%).Followup for 2 to 12 months sho

关键词： Intracranial aneurysm Anterior cerebral artery endovascular surgery Embolism Treatment outcome

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Epigenetic regulation of SARS-Cov-2 spike protein modulates cellular viability and nascent RNA transcription in neuronal cells

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Genes & Diseases 2024年第2期11卷 535-538页

作者： Xi Kong Peng Lu Jinyue Zhang Zheng Bao Chenghao Kuang Bingqing Xie Jianhua Peng Ning Ma Yong Jiang Shigang Yin Laboratory of neurological Diseases and Brain Function The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan 646000China Institute of Epigenetics and Brain Science Southwest Medical UniversityLuzhouSichuan 646000China department of neurosurgery The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan 646000China Inflammation and Allergic Diseases Research Unit The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan 646000China

SARS-CoV-2 has been demonstrated to be highly susceptible to neuron-and glial-like cells,1 but there is no consensus regarding how the virus affects neurons following *** is therefore unknown if and how SARS-CoV-2 maintains the homeostasis of neuronal ***,we revealed that the receptor-binding domain(RBD)of the SARS-CoV-2 spike protein acted as an extracellular remodeling component to undermine epigenetic regulation,perturbnascentRNA(nsRNA)transcription,promote mitochondrial biogenesis,and increase cellular viability in SH-SY5Y cells.

关键词： invasion homeostasis maintain

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Neurosurgical and pharmacological management of dystonia

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World Journal of Psychiatry 2024年第5期14卷 624-634页

作者： Ali Ahmed Mohamed Steven Faragalla Asad Khan Garrett Flynn Gersham Rainone Phillip Mitchell Johansen Brandon Lucke-Wold Charles E Schmidt College of Medicine Florida Atlantic UniversityBoca RatonFL 33431United States department of neurosurgery and Brain Repair University of South FloridaTampaFL 33606United States department of neurosurgery University of FloridaGainesvilleFL 32611United States

Dystonia characterizes a group of neurological movement disorders characterized by abnormal muscle movements,often with repetitive or sustained contraction resulting in abnormal *** types of dystonia present based on the affected body regions and play a prominent role in determining the potential efficacy of a given *** most patients afflicted with these disorders,an exact cause is rarely identified,so treatment mainly focuses on symptomatic *** agents,such as oral anticholinergic administration and botulinum toxin injection,play a major role in the initial treatment of *** more severe and/or refractory cases,focal areas for neurosurgical intervention are identified and targeted to improve quality of *** brain stimulation(DBS)targets these anatomical locations to minimize dystonia *** ablation procedures and peripheral denervation surgeries also offer potential treatment to patients who do not respond to *** management options grant providers and patients the ability to weigh the benefits and risks for each individual patient *** review article explores these pharmacological and neurosurgical management modalities for dystonia,providing a comprehensive assessment of each of their benefits and shortcomings.

关键词： Botulinum toxin Magnetic resonance imaging-guided focused ultrasound Surgical ablation Deep brain stimulation Peripheral denervation surgery Antipsychotics

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Piezo1 as a potential player in intracranial hemorrhage:From perspectives on biomechanics and hematoma metabolism

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Journal of Biomedical Research 2024年第5期38卷 436-447页

作者： Tianle Jin Maoxing Fei Shiqiao Luo Handong Wang department of neurosurgery Nanjing BenQ Medical Centerthe Affiliated BenQ Hospital of Nanjing Medical UniversityNanjingJiangsu 210019China department of neurosurgery Nanjing Jinling Hospitalthe Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210002China department of neurosurgery the Affiliated Jinling Hospital of Nanjing Medical UniversityNanjingJiangsu 210002China

Intracranial hemorrhage(ICH)causes numerous neurological deficits and deaths worldwide each year,leaving a significant health burden on the *** pathophysiology of ICH is complicated and involves both primary and secondary ***,as the primary pathology of ICH,undergoes metabolism and triggers biochemical and biomechanical alterations in the brain,leading to the secondary *** endeavors mainly aimed at biochemical-initiated mechanisms for causing secondary injury,which have made limited progress in recent years,although ICH itself is also highly *** discovery of the mechanically-activated cation channel Piezo1 provides a new avenue to further explore the mechanisms underlying the secondary *** current article reviews the structure and gating mechanisms of Piezo1,its roles in the physiology/pathophysiology of neurons,astrocytes,microglia,and bone-marrow-derived macrophages,and especially its roles in erythrocytic turnover and iron metabolism,revealing a potential interplay between the biomechanics and biochemistry of hematoma in ***,these advances provide deeper insights into the secondary injury of ICH and lay the foundations for future research.

关键词： biomechanics hematoma intracranial hemorrhage Piezo1 secondary injury

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Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage

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Stroke & Vascular Neurology 2024年第4期9卷 446-456,I0147页

作者： Yunke Li Sung-Min Cho Radhika Avadhani Hassan Ali Yi Hao Santosh B Murthy Joshua N Goldstein Fan Xia Xin Hu Natalie L Ullman Issam Awad Daniel Hanley Wendy C Ziai The George Institute for Global Health BeijingChina department of Neurology Division of Neurocritical CareJohns Hopkins Medical InstitutionsBaltimoreMarylandUSA department of Neurology Division of Brain Injury OutcomesJohns Hopkins Medical Institutions CampusBaltimoreMarylandUSA department of Neurology Weill Cornell Medical CollegeNew YorkNew YorkUSA department of Emergency Medicine Massachusetts General HospitalBostonMassachusettsUSA department of neurosurgery West China Hospital of MedicineChengduSichuanChina department of neurosurgery University of Chicago Pritzker School of MedicineChicagoIllinoisUSA

Background Minimally invasive surgery(MIS)for spontaneous supratentorial intracerebral haemorrhage(ICH)is controversial but may be beneficial if end-of-treatment(EOT)haematoma volume is reduced to≤15 *** explored whether MRI findings of cerebral small vessel disease(CSVD)modify the effect of MIS on long-term *** Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation(MISTIE)*** tested for heterogeneity in the effects of MIS and MIS+EOT volume≤15 mL on the trial’s primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable *** Of 499 patients enrolled in MISTIE III,288 patients had MRI,149(51.7%)randomised to MIS and 139(48.3%)to standard medical care(SMC).Median(IQR)ICH volume was 42(30–53)*** the full MRI cohort,there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores(all P_(interaction)>0.05).In 94 MIS patients with EOT ICH volume≤15 mL,significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score<2(OR,0.14(0.05–0.42);P_(interaction)=0.006),absence of lacunes(OR,0.37(0.18–0.80);P_(interaction)=0.02)and absence of severe white matter hyperintensities(WMHs)(OR,0.22(0.08–0.58);P_(interaction)=0.03).Conclusions Following successful haematoma reduction by MIS,we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe *** features may have utility for prognostication and patient selection in clinical trials of MIS.

关键词： Surgery surgery absence

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