Last update 21 Mar 2024

Giant Axonal Neuropathy

Last update 21 Mar 2024

Basic Info

Synonyms

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

+ [17]

Introduction

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).

Drugs associated with Giant Axonal Neuropathy

AAV9-GAN gene therapy(Pfizer Inc.)

Target-

Mechanism-

Active Org.

Pfizer Inc.

Originator Org.

Pfizer Inc.

Active Indication

Giant Axonal Neuropathy

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

scAAV9/JeT-GAN

Target-

Mechanism

Gene transference

Active Org.-

Originator Org.

The University of Texas Southwestern Medical Center

Active Indication-

Inactive Indication

Giant Axonal Neuropathy

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Giant Axonal Neuropathy

NCT02362438 / Active, not recruitingPhase 1

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.

Start Date24 Apr 2015

Sponsor / Collaborator

Taysha Gene Therapies, Inc.

[+1]

NCT03333200 / RecruitingNot ApplicableIIT

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.

Start Date11 Jan 2012

Sponsor / Collaborator

University of Pittsburgh

NCT01503125 / TerminatedNot Applicable

Clinical Study of Giant Axonal Neuropathy

Giant Axonal Neuropathy (GAN) is a devastating and rare childhood disease. Children with GAN develop increasing muscle weakness, impaired sensation, and at times mental retardation. GAN starts in infancy, leads to significant disability, and typically leads to death within the first 30 years of life. GAN is caused by a defect in the "gigaxonin" (GAN) gene, resulting in pathologically enlarged and dysfunctional nerves. Currently, there is no effective therapy. To find out what medications can help patients with GAN, the investigators have to conduct clinical trials. In this study, the investigators propose to prepare for future clinical trials and will invite GAN patients to join our research effort.
The investigators will examine them regularly to better understand their disease. The visits will include questions, a physical exam, blood drawing, a lumbar puncture, and a skin biopsy. The visits will also include tests that assess the electrical conductivity of the patients' nerves as well as a test to measure the patients' brain wave activity. In addition, the investigators will be performing tests to evaluate the patients' motor function, their vision, and thinking ability. Identifying an effective GAN treatment is very important because there is currently none. Clinical trials are the only way to decide whether a new treatment works in GAN patients or not.
With the future objective of conducting clinical trials in GAN, the proposed project has three specific aims. The first is to plan for clinical trials by developing reliable outcome measures, and establishing the infrastructure needed to carry out efficient clinical trials. The second is to further characterize the patient population from a clinical and molecular point of view, and the third aim is to utilize the information gathered in this study to further pre-clinical GAN drug development to select candidate drugs.

Start Date01 Dec 2011

Sponsor / Collaborator

Columbia University

[+1]

100 Clinical Results associated with Giant Axonal Neuropathy

100 Translational Medicine associated with Giant Axonal Neuropathy

0 Patents (Medical) associated with Giant Axonal Neuropathy

383

Literatures (Medical) associated with Giant Axonal Neuropathy

13 Jan 2024·Journal of Alzheimer's disease : JAD

O-GlcNAcylation and Its Roles in Neurodegenerative Diseases.

Review

Author: 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.

07 Nov 2023·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

Author: 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.

31 Oct 2023·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

Author: 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.

News (Medical) associated with Giant Axonal Neuropathy

19 Feb 2024

·www.globenewswire.com

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.

Gene TherapyLicense out/in

16 Nov 2023

·endpts.com

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.

License out/in

22 Sep 2023

·www.biospace.com

FDA Regulatory Gauntlet Isn’t Getting Any Easier, Just Ask These Companies

Pictured: Stop sign in front of FDA headquarters/Sarah Silbiger/Getty Images Several companies this week got stark reminders that the FDA’s regulatory gauntlet is difficult to navigate in terms of getting treatments approved. Though it received backing from the Pulmonary-Allergy Drugs Advisory Committee in May, the FDA on Tuesday rejected ARS Pharmaceuticals’ neffy as a nasal spray for allergic reactions—a reminder that the regulator doesn’t have to follow the advice of its advisory committees. ARS plans to Formal Dispute Resolution Request appealing the FDA’s Complete Response Letter (CRL). On Thursday, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 19-0 against Intarcia Therapeutics’ ITCA 650 implantable drug-device combination for the treatment of type 2 diabetes. The advisory committee defeat is the latest in ITCA 650’s troubled regulatory history, which has included two CRLs. Taysha this week dropped its lead experimental gene therapy candidate for giant axonal neuropathy after the FDA reiterated the need for a randomized, double-blind, placebo-controlled trial. Adding insult to injury, in Tuesday’s announcement Taysha reported that Astellas will not be exercising its option to obtain an exclusive license to the therapy. After facing regulatory roadblocks, BeiGene reported this week that Novartis returned the former’s anti-PD-1 antibody, with the cancer-focused biotech regaining worldwide rights to develop, manufacture and commercialize tislelizumab. In a separate announcement, BeiGene announced that the FDA accepted for review a Biologics License Application for tislelizumab as a first-line treatment for patients with unresectable, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma. Other companies seem to have learned from their regulatory setbacks and have course corrected. Bouncing back from two CRLs, Alvotech saw its Biologics License Application for Humira biosimilar AVT02 accepted by the regulator with a target action date of Feb. 24, 2024. And, following a Type A meeting with the FDA, Mesoblast this week said it now has clarity about the next steps in demonstrating the effectiveness of its twice-rejected cell therapy in acute graft-versus-host disease. Seven months after it won accelerated approval, Travere Therapeutics this week came up short on a confirmatory Phase III study for its kidney disease drug sparsentan, which narrowly missed a key endpoint. Travere now says it will meet with regulators and expects to submit a supplemental New Drug Application in the first half of 2024 for full approval. The company’s shares plummeted more than 40% following the news. However, progress was made in several late-stage cancer trials this week. Merck, Seagen and Astellas—which are collaborating on a drug combination to treat locally advanced and metastatic urothelial cancer—announced Friday that their Phase III trial met dual primary endpoints. The same day, AstraZeneca and Daiichi Sankyo reported that their antibody-drug conjugate improved progression-free survival with a “trend in improvement” for overall survival in a late-stage breast cancer study—as they look to challenge Gilead’s Trodelvy. Finally, in honor of World Cancer Research Day (Sept. 24), BioSpace this week took a deep dive into 10 therapeutic candidates with the potential to change the treatment landscape for lung, breast, colorectal and other cancers. Greg Slabodkin is the News Editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

Phase 3Clinical ResultCell TherapyLicense out/in

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