Last update 01 Nov 2024

DOK7

Last update 01 Nov 2024

Basic Info

Synonyms

C4orf25, docking protein 7, Dok-7

+ [5]

Introduction

Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. Induces autophosphorylation of MUSK.

Drugs associated with DOK7

AMP-101

Target

DOK7

Mechanism

DOK7 stimulants

Active Org.

Amplo Biotechnology, Inc.

Originator Org.

University of Tokyo

Active Indication

Myasthenic Syndromes, Congenital

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

WO2022013554

Patent Mining

Target

DOK7

Mechanism-

Active Org.

Oxford University Innovation Ltd.

Originator Org.

Oxford University Innovation Ltd.

Active Indication

Rare Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DOK7

100 Translational Medicine associated with DOK7

0 Patents (Medical) associated with DOK7

207

Literatures (Medical) associated with DOK7

01 Oct 2024·Biochemical and Biophysical Research Communications

A class of chemical compounds enhances clustering of muscle nicotinic acetylcholine receptor in cultured myogenic cells

Article

Author: Tomita, Hiroyuki ; Sawada, Ryusuke ; Nakashima, Hiroaki ; Masuda, Akio ; Ohno, Kinji ; Hosono, Yasuyuki ; Imagama, Shiro ; Miyairi, Yuichi ; Sato, Ayato ; Ito, Mikako ; Ishii, Hisao ; Inoue, Taro ; Ohkawara, Bisei

Neuromuscular signal transmission is affected in various diseases including myasthenia gravis, congenital myasthenic syndromes, and sarcopenia. We used an ATF2-luciferase system to monitor the phosphorylation of MuSK in HEK293 cells introduced with MUSK and LRP4 cDNAs to find novel chemical compounds that enhanced agrin-mediated acetylcholine receptor (AChR) clustering. Four compounds with similar chemical structures carrying benzene rings and heterocyclic rings increased the luciferase activities 8- to 30-folds, and two of them showed continuously graded dose dependence. The effects were higher than that of disulfiram, a clinically available aldehyde dehydrogenase inhibitor, which we identified to be the most competent preapproved drug to enhance ATF2-luciferase activity in the same assay system. In C2C12 myotubes, all the compounds increased the area, intensity, length, and number of AChR clusters. Three of the four compounds increased the phosphorylation of MuSK, but not of Dok7, JNK. ERK, or p38. Monitoring cell toxicity using the neurite elongation of NSC34 neuronal cells as a surrogate marker showed that all the compounds had no effects on the neurite elongation up to 1 μM. Extensive docking simulation and binding structure prediction of the four compounds with all available human proteins using AutoDock Vina and DiffDock showed that the four compounds were unlikely to directly bind to MuSK or Dok7, and the exact target remained unknown. The identified compounds are expected to serve as a seed to develop a novel therapeutic agent to treat defective NMJ signal transmission.

01 Sep 2024·Pediatric Neurology

Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients

Article

Author: Van Parijs, Vinciane ; Herdewyn, Sarah ; Dubuisson, Nicolas ; Paquay, Stéphanie ; De Bleecker, Jan ; Smeets, Nathalie ; Gheldof, Alexander ; Deconinck, Nicolas ; Remiche, Gauthier ; Dequeker, Bart ; Vanlander, Arnaud ; Bissay, Véronique ; Maldonado Slootjes, Sofia ; Dontaine, Pauline ; Alonso-Jimenez, Alicia ; Hansen, Isabelle ; De Waele, Liesbeth ; De Ridder, Willem ; Claeys, Kristl G ; Peirens, Geertrui ; Seneca, Sara ; Régal, Luc ; Beysen, Diane ; Poleur, Margaux

BACKGROUNDCongenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022.METHODSData were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis.RESULTSWe identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype.CONCLUSIONSThis is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.

01 Jul 2024·Aging Cell

Prevention of age‐related neuromuscular junction degeneration in sarcopenia by low‐magnitude high‐frequency vibration

Article

Author: Bao, Zhengyuan ; Qin, Ling ; Chow, Simon Kwoon‐Ho ; Xu, Zhihong ; Yip, Benjamin Hon Kei ; Wong, Ronald Man Yeung ; Jiang, Qing ; Liu, Chaoran ; Cheung, Wing‐Hoi ; Long, Yufeng ; Chai, Senlin ; Cui, Can ; Rubin, Clinton

AbstractNeuromuscular junction (NMJ) degeneration is one of pathological factors of sarcopenia. Low‐magnitude high‐frequency vibration (LMHFV) was reported effective in alleviating the sarcopenia progress. However, no previous study has investigated treatment effects of LMHFV targeting NMJ degeneration in sarcopenia. We first compared morphological differences of NMJ between sarcopenic and non‐sarcopenic subjects, as well as young and old C57BL/6 mice. We then systematically characterized the age‐related degeneration of NMJ in SAMP8 against its control strain, SAMR1 mice, from 3 to 12 months old. We also investigated effects of LMHFV in SAMP8 on the maintenance of NMJ during the onset of sarcopenia with respect to the Agrin‐LRP4‐MuSK‐Dok7 pathway and investigated the mechanism related to ERK1/2 signaling. We observed sarcopenic/old NMJ presented increased acetylcholine receptors (AChRs) cluster fragmentation and discontinuity than non‐sarcopenic/young NMJ. In SAMP8, NMJ degeneration (morphologically at 6 months and functionally at 8 months) was observed associated with the sarcopenia onset (10 months). SAMR1 showed improved NMJ morphology and function compared with SAMP8 at 10 months. Skeletal muscle performance was improved at Month 4 post‐LMHFV treatment. Vibration group presented improved NMJ function at Months 2 and 6 posttreatment, accompanied with alleviated morphological degeneration at Month 4 posttreatment. LMHFV increased Dok7 expression at Month 4 posttreatment. In vitro, LMHFV could promote AChRs clustering in myotubes by increasing Dok7 expression through suppressing ERK1/2 phosphorylation. In conclusion, NMJ degeneration was observed associated with the sarcopenia onset in SAMP8. LMHFV may attenuate NMJ degeneration and sarcopenia progression by increasing Dok7 expression through suppressing ERK1/2 phosphorylation.

News (Medical) associated with DOK7

17 Oct 2024

·www.prnewswire.com

Amplo Biotechnology Announces Three Presentations at the European Society of Gene and Cell Therapy 31st Annual Congress

SAN DIEGO, Oct. 17, 2024 /PRNewswire/ -- Amplo Biotechnology, a biotechnology company developing genetic medicines for the treatment of neuromuscular diseases, announced the presentation of three posters at the European Society of Gene and Cell Therapy (ESGCT) 31st Annual Congress, taking place from October 22-25, 2024, in Rome, Italy. Amplo will feature three poster presentations detailing its platform approach to developing programmatic gene therapies, new preclinical data for Dok-7 gene therapy (AMP-101), and lead candidate activities for its novel Collagen Q therapy (AMP-201). "We are pleased to present data at ESGCT demonstrating the potential of our lean drug development strategy that supports the commercial viability of gene therapies in rare- and super-rare diseases by leveraging the ecosystem's knowledge," said Patricio Sepulveda, PhD MBA, Chief Executive Officer at Amplo Biotechnology. Details for the poster presentations: Abstract Title: Development of a platform gene therapy approach for Congenital Myasthenic Syndromes Presenting Author: Patricio V. Sepulveda S., PhD MBA Date: Tuesday, October 22, 2024 Abstract Title: Pre-clinical development of gene augmentation therapy to restore Acetylcholinesterase activity in Collagen Q Congenital Myasthenic Syndrome using a platform approach to AAV gene therapy development. Presenting Author: Claudia Canzonetta, PhD Date: Tuesday, October 22, 2024 Abstract Title: The pre-clinical development of gene augmentation therapy to stabilize the neuromuscular junction in Dok-7 Congenital Myasthenic Syndrome reveals a mechanism of action that has the potential to treat many neuromuscular junction diseases using the same vector. Presenting Author: Paul Al Hawkins Date: Wednesday, October 23, 2024 About Amplo Biotechnology Amplo is a late, pre-clinical genetic medicines company focused on therapies for rare and super-rare diseases. SOURCE Amplo Biotechnology WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Gene Therapy

29 May 2023

·www.prnewswire.com

Amplo Biotechnology Secures Fast Track STTR Funding for AMP-201, a Promising Gene Therapy Targeting Collagen Q Deficiency

SAN DIEGO, May 29, 2023 /PRNewswire/ -- Amplo Biotechnology, a leading US-based biotech company dedicated to developing innovative AAV-based gene therapies for neuromuscular junction disorders announced the award of a Fast Track Phase I/II STTR grant from the NIH-NIAMS. This highly competitive grant will provide substantial funding for the advancement of AMP-201, an AAV-ColQ gene therapy designed to address the severe congenital myasthenic syndrome (CMS) caused by Collagen Q (ColQ) Deficiency. Under an exclusive licensing agreement, Amplo Biotechnology has gained access to AAV-ColQ data developed by Professor Kinji Ohno's laboratory at Nagoya University, which forms the basis of AMP-201. In the Fast Track STTR project, Amplo will collaborate with Professor Ricardo Maselli, a CMS expert neurologist and researcher at UC-Davis. Amplo Biotechnology's development of AMP-201 builds upon it's progression of AMP-101, an AAV-DOK7 gene therapy targeting Dok-7 congenital myasthenic syndrome, which Amplo expects to bring to clinical trial in 2024. Upon demonstrating initial safety and efficacy, the company plans to expand into other neuromuscular conditions, leveraging the vast potential of AMP-101 and AMP-201 to significantly enhance the quality of life for the majority of CMS patients. "Amplo is thrilled to collaborate with UC-Davis in the development of AMP-201, addressing the critical unmet needs of patients suffering from ColQ CMS. By combining the power of Amp-101 and AMP-201, we are confident in our ability to revolutionize the lives of CMS patients," expressed Dr. Patricio Sepulveda, CEO of Amplo Biotechnology, who holds a Ph.D. in the field and an MBA. About Amplo Biotechnology: Amplo Biotechnology is a leading late-stage preclinical AAV gene therapy company, committed to leveraging gene therapy advancements to improve neuromuscular junction function across various medical conditions. The company's flagship program, AMP-101, has successfully undergone rigorous preclinical studies, enabling the submission of a Clinical Trial Application in the UK for Dok7 CMS. Amplo Biotechnology's technologies are rooted in ground-breaking research conducted at renowned institutions such as the University of Tokyo, Oxford University, and Nagoya University. For media inquiries and further information, please contact: Patricio Sepulveda [email protected] SOURCE Amplo Biotechnology

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