Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ). We exploited the proprietary NMJ-targeting signals of ColQ to treat congenital myasthenia and to explore the mechanisms of autoimmune myasthenia gravis (MG). Mutations in COLQ cause congenital endplate AChE deficiency (CEAD). First, a single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq−/− mice normalized motor functions, synaptic transmission, and partly the NMJ ultrastructure. Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs. Second, MuSK antibody-positive MG accounts for 5-15 % of MG. In vitro overlay of AChE/ColQ to muscle sections of Colq−/− mice, as well as in vitro plate-binding of MuSK to ColQ, revealed thatMuSK-IgG blocks binding of ColQ to MuSK in a dose-dependent manner. Passive transfer of MuSK-IgG to wild-type mice markedly reduced the size and intensity of ColQ signals at NMJs. MuSK-IgG thus interferes with binding of ColQ to MuSK. Elucidation of molecular mechanisms of specific binding of ColQ to NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq−/− mice and also to reveal underlying mechanisms of anti-MuSK-MG.

2013-02-01·Revue neurologique4区 · 医学

Syndromes myasthéniques congénitaux : difficultés diagnostiques, évolution et pronostic, thérapeutique L’expérience du réseau national « Syndromes Myasthéniques Congénitaux »

4区 · 医学

Review

作者: E Fournier ; M Fardeau ; P Laforêt ; D Hantaï ; N Romero ; S Nicole ; A Béhin ; D Sternberg ; B Eymard ; P Richard ; T Stojkovic ; L Servais

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Network: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine.

2012-07-01·Molecular therapy : the journal of the American Society of Gene Therapy1区 · 医学

1区 · 医学

Article

作者: Akio Masuda ; Takashi Okada ; Yumi Suzuki ; Mikako Ito ; Kinji Ohno ; Eric Krejci ; Takayasu Fukudome ; Shin'ichi Takeda ; Toshiro Yoshimura

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ). Congenital defects of ColQ cause endplate AChE deficiency and myasthenic syndrome. A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq(-/-) mice recovered motor functions, synaptic transmission, as well as the morphology of the NMJ. ColQ-tailed AChE was specifically anchored to NMJ and its amount was restored to 89% of the wild type. We next characterized the molecular basis of this efficient recovery. We first confirmed that ColQ-tailed AChE can be specifically targeted to NMJ by an in vitro overlay assay in Colq(-/-) mice muscle sections. We then injected AAV1-COLQ-IRES-EGFP into the left tibialis anterior and detected AChE in noninjected limbs. Furthermore, the in vivo injection of recombinant ColQ-tailed AChE protein complex into the gluteus maximus muscle of Colq(-/-) mice led to accumulation of AChE in noninjected forelimbs. We demonstrated for the first time in vivo that the ColQ protein contains a tissue-targeting signal that is sufficient for anchoring itself to the NMJ. We propose that the protein-anchoring strategy is potentially applicable to a broad spectrum of diseases affecting extracellular matrix molecules.

项与 COLQ gene therapy (Amplo Biotechnology) 相关的新闻（医药）

2024-10-17

·PRNewswire

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

基因疗法

2023-05-29

·PRNewswire

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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