更新于：2024-05-01

Giant Axonal Neuropathy

巨轴索神经病

更新于：2024-05-01

基本信息

别名

Axonal Neuropathy, Giant、Axonal Neuropathy, Giant (GAN)、GAN

+ [17]

简介

Rare autosomal recessive disorder of INTERMEDIATE FILAMENT PROTEINS. The disease is caused by mutations in the gene that codes gigaxonin protein. The mutations result in disorganization of axonal NEUROFILAMENT PROTEINS, formation of the characteristic giant axons, and progressive neuropathy. The clinical features of the disease include early-onset progressive peripheral motor and sensory neuropathies often associated with central nervous system involvement (INTELLECTUAL DISABILITY, seizures, DYSMETRIA, and CONGENITAL NYSTAGMUS).

关联

项与巨轴索神经病相关的药物

AAV9-GAN gene therapy(Pfizer Inc.)

靶点-

作用机制-

在研机构

Pfizer Inc.

原研机构

Pfizer Inc.

在研适应症

巨轴索神经病

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

scAAV9/JeT-GAN

靶点-

作用机制

基因转移

在研机构-

原研机构

The University of Texas Southwestern Medical Center

在研适应症-

非在研适应症

巨轴索神经病

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与巨轴索神经病相关的临床试验

ChiCTR-INR-17010324 / SuspendedIIT

Clinical Study on TCM Diagnosis and Treatment Scheme of Acute Drug-Induced Liver Injury by Anti-AIDS Drugs (Gan-Dan Damp-Heat Syndrome and Qi-Blood Deficiency Syndrome)

开始日期2017-09-01

申办/合作机构-

NCT02362438 / Active, not recruiting临床1期

A Phase I Study of Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy

Title: Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy
Background:
- The Gigaxonin gene lets the body make a protein chemical called Gigaxonin. Nerves need Gigaxonin to work properly. Giant Axonal Neuropathy (GAN) causes a shortage of functional Gigaxonin. Nerves stop working normally in people with GAN. This causes problems with walking and sometimes with eating, breathing, and many other activities. GAN has no cure. Over time, GAN can shorten a person s life. Researchers want to see if a gene transfer treatment may help people with GAN.
Objectives:
- To see if a gene transfer is safe and shows potential to help people with GAN.
Eligibility:
- People age 3 and older with GAN.
Design:
For 1 month following gene transfer participants must live full-time within 100 miles of the NIH.
Participants will be screened by phone and in person. They will take many tests. Some are listed below. Their medical records will be reviewed. Their caregivers may be contacted.
Participants will have a total of about 27 visits, weekly, monthly, and then yearly over 15 years. They will include many of the tests below.
Physical and nervous system exams.
Blood, urine, and stool samples.
Nerve, lung, heart, and eye tests.
Questionnaires.
MRI scans, nerve biopsies, and spinal taps. Participants will be sedated for some tests.
Speech, memory, muscle, and mobility tests.
Skin biopsy (small sample removed).
Participants will take many medicines. Some require intravenous lines.
Participants will get the gene transfer through an injection by spinal tap into their cerebrospinal fluid, which flows around the brain and spinal cord. The genes are packed in a modified virus that carries the genes to cells in their body. Participants safety is not guaranteed.

开始日期2015-04-24

申办/合作机构

Taysha Gene Therapies, Inc.

[+1]

NCT03333200 / RecruitingN/AIIT

Longitudinal Study of Neurodegenerative Disorders

The purpose of this study is to understand the course of rare genetic disorders that affect the brain. This data is being analyzed to gain a better understanding of the progression of the rare neurodegenerative disorders and the effects of interventions.

开始日期2012-01-11

申办/合作机构

University of Pittsburgh

100 项与巨轴索神经病相关的临床结果

登录后查看更多信息

100 项与巨轴索神经病相关的转化医学

登录后查看更多信息

0 项与巨轴索神经病相关的专利（医药）

登录后查看更多信息

383

项与巨轴索神经病相关的文献（医药）

2024-01-13·Journal of Alzheimer's disease : JAD

O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.

Review

作者: Pengyang Du ; Xiaomin Zhang ; Xia Lian ; Christian Hölscher ; Guofang Xue

As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.

2023-11-07·Proceedings of the National Academy of Sciences of the United States of America

The CRL3^gigaxonin ubiquitin ligase-USP15 pathway governs the destruction of neurofilament proteins.

Article

作者: Hyoung-Min Park ; Ly Le ; Thao T Nguyen ; Ki Hong Nam ; Alban Ordureau ; J Eugene Lee ; Thang Van Nguyen

Giant axonal neuropathy (GAN) is caused by mutations in the GAN gene encoding for gigaxonin (GIG), which functions as an adaptor of the CUL3-RBX1-GIG (CRL3^GIG) E3 ubiquitin ligase complex. The pathological hallmark of GAN is characterized by the accumulation of densely packed neurofilaments (NFs) in the axons. However, there are fundamental knowledge gaps in our understanding of the molecular mechanisms by which the ubiquitin-proteasome system controls the homeostasis of NF proteins. Recently, the deubiquitylating enzyme USP15 was reported to play a crucial role in regulating ubiquitylation and proteasomal degradation of CRL4^CRBN substrate proteins. Here, we report that the CRL3^GIG-USP15 pathway governs the destruction of NF proteins NEFL and INA. We identified a specific degron called NEFL^L12 degron for CRL3^GIG. Notably, mutations in the C-terminal Kelch domain of GIG, represented by L309R, R545C, and C570Y, disrupted the binding of GIG to NEFL and INA, leading to the accumulation of these NF proteins. This accounts for the loss-of-function mutations in GAN patients. In addition to regulating NFs, CRL3^GIG also controls actin filaments by directly targeting actin-filament-binding regulatory proteins TPM1, TPM2, TAGLN, and CNN2 for proteasomal degradation. Thus, our findings broadly impact the field by providing fundamental mechanistic insights into regulating extremely long-lived NF proteins NEFL and INA by the CRL3^GIG-USP15 pathway and offering previously unexplored therapeutic opportunities to treat GAN patients and other neurodegenerative diseases by explicitly targeting downstream substrates of CRL3^GIG.

2023-10-31·Proceedings of the National Academy of Sciences of the United States of America

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Article

作者: Yvette C Wong ; Nirupa D Jayaraj ; Tayler B Belton ; George C Shum ; Hannah E Ball ; Dongjun Ren ; Abigail L D Tadenev ; Dimitri Krainc ; Robert W Burgess ; Daniela M Menichella

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

项与巨轴索神经病相关的新闻（医药）

2024-03-16

·精准药物

【Cell 】全新靶点MKK4 抑制剂已进入Ⅰ期临床试验，风险与机遇共存

导读肝脏具有独特的再生能力，在发生损伤后肝细胞迅速启动增殖程序，进行损伤修复。然而，在急性或慢性肝病中以及肝切除术后，肝细胞再生能力往往受损，无法恢复肝脏质量和功能。疾病相关的微环境通过复杂的细胞间互作降低肝细胞再生能力，但人们对潜在的分子机制知之甚少。德国图宾根大学的 Lars Zender 团队在肝再生领域深耕十余年，2013 年曾在 Cell 报道通过体内 RNAi 筛选鉴定出丝裂原活化蛋白激酶激酶 4（MKK4）是肝细胞再生的关键调控因子。压力信号活化 MKK4，进而活化 JNK1/2/3 和 p38，而 MKK4 的敲低上调 MKK7/JNK1 活化的 ATF2、ELK1 促再生转录程序，从而恢复肝细胞再生能力。尽管许多实验室以及初创公司进行 MKK4 抑制剂的开发，其靶向性、疗效仍不理想。2024 年 3 月 14 日，来自德国图宾根大学的 Lars Zender 和新加坡南洋理工大学等研究团队联合在 Cell 发表了题为 First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure 的文章。在证明系统性 MKK4 的抑制促肝再生的基础上，开发了强效、选择性的 MKK4 抑制剂，在多种动物模型中证明了安全有效性，并进入 Ⅰ 期临床试验。图源：Cell研究思路作者原创创新点1. 基于结构学的开发使抑制剂具有高选择性；2. 通过严谨的临床前实验证明 HRX215 具有良好的耐受性和安全性；3. HRX215 具有强大的促肝再生能力，为更大范围肝肿瘤切除以及肝小叶移植提供基础。主要研究内容1. 敲低 MKK4 促进小鼠肝脏再生，并且长期安全为了模拟 MKK4 抑制剂的系统作用，研究员构建了 dox 诱导的 MKK4 敲低鼠（CAG-rtTA; TRE-shMKK4），dox 诱导后进行部分肝切除（PH），显示 MKK 的敲低使 Ki67 阳性细胞增多，证明 MKK4 的系统性抑制促进肝再生。Dox 处理 12 个月后，shMKK4 鼠的体重以及组织病理学形态正常，表明了 MKK4 抑制剂的安全性。Figure 1. MKK4 的敲低促进小鼠肝脏再生，并且长期安全（图源：Cell ）2. 强效、选择性小分子 MKK4 抑制剂的开发和表征首先，研究员开始进行药物发现。因为受限于尚无足够分辨率的蛋白结构，他们从已报道的蛋白激酶抑制剂的脱靶谱中，选择了对 MKK4 具高脱靶亲和力的 vemurafenib（BRAFV600E 抑制剂）作为原型，经过 C 环置换、烷基磺酰胺修饰后产生二代抑制剂；接着解析了与激酶结构域的 NMR 结构，基于经验对 C 环修饰后，最终将选择性最高的 HRX215 作为临床候选药物。经过细胞和体内实验表明，HRX215 具细胞膜通透性，并且半衰期（3.4-3.9 h）允许进一步的体内药理学分析。Figure 2. 强效、选择性小分子 MKK4 抑制剂的开发和表征（图源：Cell ）3. HRX215 促进肝增殖、稳定肝细胞接着，研究员在体内探究 HRX215 的药效、安全性。与敲低 MKK4 一致，HRX215 以剂量依赖性方式促进 PH 后的肝细胞增殖，并且不诱导未手术肝的增殖；此外，HRX215 处理与 MKK4 敲低的肝的术后表达谱高度相关，表明 HRX215 的选择性。除了促进肝细胞增殖，肝 MKK4 的抑制具有肝保护功能。TUNEL 显示，HRX215 抑制 CCl4 诱导的肝损伤模型中的肝细胞凋亡；凋亡相关磷酸化蛋白阵列显示，HRX215 抑制 PH 后的肝细胞凋亡。最后评估安全性。通过血浆、肝脏代谢组学显示，HRX215 仅引起自身代谢物的变化；GAN-NASH 模型中，12 周的 HRX215 治疗不增加肿瘤数量，甚至降低肿瘤尺寸，但不影响异常增生，表明 HRX215 抑制肿瘤进展。Figure 3. HRX215 促进 PH 后的肝细胞增殖，减轻 CCl4 肝损伤模型中细胞凋亡（图源：Cell ）Figure 4. HRX215 长期治疗的安全性（图源：Cell ）4. HRX215 阻止 PHLF为了更好地验证人肝切除术后的情况，作者使用猪 PH 模型，其中 85% 肝切除会引发肝切除术后肝衰竭（PHLF），是严重的临床问题。与小鼠模型一致，HRX215 增加再生肝的体积，促进肝细胞增殖。在 85% 肝切除模型中，HRX215 有效阻止急性肝衰竭的发生（ICP 增加），维持肝的正常功能（代谢、合成凝血蛋白）。重要的是，HRX215 治疗阻止术后昏迷，以及肝脏变小、灌注不足，表明 HRX215 介导的肝再生有效阻止 85% 肝切除术后的致命 PHLF。Figure 5. HRX215 增加猪 85% 肝切除术后的肝再生（图源：Cell ）Figure 6. HRX215 阻止 85% 肝切除术后的肝衰竭（图源：Cell ）5. HRX215 具有良好的安全性、药代动力学特征最后在 48 名男性志愿者中进行Ⅰ期临床试验，显示 HRX215 不会引发不良反应。使用 LC-MS/MS 研究药代动力学，发现 HRX215 被快速吸收，达到最大浓度后以双相方式被清除；暴露量与剂量正相关；进食后给药延迟吸收但提高生物利用度。Figure 7. HRX215 的首次人体Ⅰ期临床试验（图源：Cell ）文章小结本文在证明系统性 MKK4 抑制剂肝再生的基础上，进行了 MKK4 小分子抑制剂的开发、临床前评估以及Ⅰ期临床毒性评估。图源：Cell参考文献：Zwirner S, et al. First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell. 2024 Mar 28;187(1-19).声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床1期临床2期

2024-02-19

·GlobeNewswire-Health Care

Taysha Gene Therapies Provides Update on Deprioritized Pipeline Programs

Feb. 15, 2024 -- Taysha Gene Therapies, Inc. (Nasdaq: TSHA) (“Taysha” or “the Company”), a clinical-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS), today provided an update on its deprioritized pipeline programs as part of an ongoing effort to help support their further potential development. Taysha has been working to find ways to advance its deprioritized programs. On November 13, 2023, Taysha terminated its existing loan and security agreement and entered into a new loan and security agreement that provides consent to allow the Company to transfer intellectual property (IP) for several deprioritized programs to third parties in a more efficient manner. The Company’s new loan and security agreement also extended its cash runway into 2026. TSHA-120: The Company initiated the transfer of the United States Food and Drug Administration Investigational New Drug (IND) application and investigational clinical trial material for TSHA-120 in giant axonal neuropathy (GAN) to clinical trial collaborator National Institute of Neurological Disorders and Stroke (NINDS), creating an opportunity for continued clinical evaluation of TSHA-120 in GAN. Additionally, the Company entered discussions with the originating advocacy organization regarding TSHA-120 in an effort to transfer rights back to the advocacy organization to move the program forward. TSHA-101: The Company transferred rights back to Queen’s University (Queen’s) for TSHA-101 in GM2 gangliosidosis, resulting in Queen’s regaining exclusive IP to the program. TSHA-104 and TSHA-112: The Company transferred rights back to the originating institution for select programs, including TSHA-104 in SURF1-associated Leigh syndrome and TSHA-112 in APBD. TSHA-118: The Company provided investigational clinical trial material for TSHA-118 in CLN1 to support an individual-patient investigator-initiated IND request from RUSH University Medical Center for the treatment of a patient with CLN1 disease. “Today’s announcement demonstrates meaningful progress to advance important development work for several deprioritized programs. Creating options for these programs has been a focus since the Company completed a management change in December 2022, and the new loan and security agreement afforded the flexibility to implement certain opportunities,” said Sean P. Nolan, Chairman and Chief Executive Officer of Taysha. “As we continue to focus on advancing our lead TSHA-102 program for the treatment of Rett syndrome, we are pleased that we can ensure these programs are provided to the right advocates, clinicians and scientific experts who can potentially move these programs forward for the benefit of patients.” The Company continues to explore potential partnerships and opportunities for its other deprioritized programs to help support their further potential development. Taysha Gene Therapies (Nasdaq: TSHA) is a clinical-stage biotechnology company focused on advancing adeno-associated virus (AAV)-based gene therapies for severe monogenic diseases of the central nervous system. Its lead clinical program TSHA-102 is in development for Rett syndrome, a rare neurodevelopmental disorder with no approved disease-modifying therapies that address the genetic root cause of the disease. With a singular focus on developing transformative medicines, Taysha aims to address severe unmet medical needs and dramatically improve the lives of patients and their caregivers. The Company’s management team has proven experience in gene therapy development and commercialization. Taysha leverages this experience, its manufacturing process and a clinically and commercially proven AAV9 capsid in an effort to rapidly translate treatments from bench to bedside. For more information, please visit www.tayshagtx.com. The content above comes from the network. if any infringement, please contact us to modify.

基因疗法引进/卖出

2023-11-16

·EndPoints

Patient foundation accuses rare disease company Taysha of violating licensing agreement

A patient group this summer accused Taysha Gene Therapies of breaching a contract to develop a therapy for an ultra-rare condition, another sign of deep tensions between the company and family foundations. In July, Hannah’s Hope Fund claimed that Taysha breached a licensing agreement that called for the company to develop a therapy for giant axonal neuropathy, an ultra-rare condition that renders patients quadriplegic and is followed by early death, according to an SEC filing on Tuesday. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.