Last update 21 Mar 2024

AP4M1

adaptor related protein complex 4 subunit mu 1

Last update 21 Mar 2024

Basic Info

Synonyms

adaptor related protein complex 4 subunit mu 1, Adaptor-related protein complex 4 subunit mu-1, AP-4 adaptor complex mu subunit

+ [10]

Introduction

Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways (PubMed:10436028, PubMed:11139587, PubMed:10066790, PubMed:11802162, PubMed:20230749). AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system (PubMed:11139587, PubMed:20230749). It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons (By similarity). Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos (PubMed:10436028, PubMed:11139587, PubMed:26544806, PubMed:20230749). The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal (By similarity).

Drugs associated with AP4M1

Self-complimentary adeno-associated virus 9 gene therapy containing codon optimized human AP4M1(CureSPG50)

Target

AP4M1

Mechanism

AP4M1 stimulants

Active Org.

CureSPG50

Originator Org.

CureSPG50

Active Indication

Spastic Paraplegia-50, Autosomal Recessive

Inactive Indication-

Drug Highest PhaseClinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with AP4M1

NCT06069687 / Active, not recruitingPhase 1IIT

A Phase 1 Open-label Intrathecal Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by a Mutation in the AP4M1 Gene

This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity.
The secondary outcome will be a preliminary exploration of efficacy of the treatment.
MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg.
The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.

Start Date11 Mar 2022

Sponsor / Collaborator

The Hospital for Sick Children

100 Clinical Results associated with AP4M1

100 Translational Medicine associated with AP4M1

0 Patents (Medical) associated with AP4M1

Literatures (Medical) associated with AP4M1

26 Jan 2024·Progress in neurobiology

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia.

Article

Author: Mario O Caracci ; Héctor Pizarro ; Carlos Alarcón-Godoy ; Luz M Fuentealba ; Pamela Farfán ; Raffaella De Pace ; Natacha Santibañez ; Viviana A Cavieres ; Tammy P Pástor ; Juan S Bonifacino ; Gonzalo A Mardones ; María-Paz Marzolo

Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

06 Jan 2024·Pediatric neurology

A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants.

Article

Author: Mehmet Akif Kilic ; Edibe Pembegul Yildiz ; Adnan Deniz ; Orhan Coskun ; Fulya Kurekci ; Ridvan Avci ; Hulya Maras Genc ; Gozde Yesil ; Sinan Akbas ; Ahmet Yesilyurt ; Bulent Kara

BACKGROUND:

Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative disorders. Our objective was to determine the clinical and molecular characteristics of patients with genetically confirmed childhood-onset HSPs and to expand the genetic spectrum for some rare subtypes of HSP.

METHODS:

We reviewed the charts of subjects with genetically confirmed childhood-onset HSP. The age at the disease onset was defined as the point at which the delayed motor milestones were observed. Delayed motor milestones were defined as being unable to hold the head up by four months, sitting unassisted by nine months, and walking independently by 17 months. If there were no delayed motor milestones, age at disease onset was determined by leg stiffness, frequent falls, or unsteady gait. Genetic testing was performed based on delayed motor milestones, progressive leg spasticity, and gait difficulty. The variant classification was determined based on the American College of Medical Genetics standard guidelines for variant interpretation. Variants of uncertain significance (VUS) were considered disease-associated when clinical findings were consistent with the previously described disease phenotypes for pathogenic variants. In addition, in the absence of another pathogenic, likely pathogenic, or VUS variant that could explain the phenotype of our cases, we concluded that the disease is associated with VUS in the HSP-causing gene. Segregation analysis was also performed on the parents of some patients to demonstrate the inheritance model.

RESULTS:

There were a total of 18 patients from 17 families. The median age of symptom onset was 18 months (2 to 84 months). The mean delay between symptom onset and genetic diagnosis was 5.8 years (5 months to 17 years). All patients had gait difficulty caused by progressive leg spasticity and weakness. Independent walking was not achieved at 17 months for 67% of patients (n = 12). In our cohort, there were two subjects each with SPG11, SPG46, and SPG 50 followed by single subject each with SPG3A, SPG4, SPG7, SPG8, SPG30, SPG35, SPG43, SPG44, SPG57, SPG62, infantile-onset ascending spastic paralysis (IAHSP), and spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). Eight novel variants in nine patients were described. Two affected siblings had a novel variant in the GBA2 gene (SPG46), and one subject each had a novel variant in WASHC5 (SPG8), SPG11 (SPG11), KIF1A (SPG30), GJC2 (SPG44), ERLIN1 (SPG62), ALS2 (IAHSP), and HACE1 (SPPRS). Among the novel variants, the variant in the SPG11 was pathogenic and the variants in the KIF1A, GJC2, and HACE1 were likely pathogenic. The variants in the GBA2, ALS2, ERLIN1, and WASHC5 were classified as VUS.

CONCLUSIONS:

There was a significant delay between symptom onset and genetic diagnosis of HSP. An early diagnosis may be possible by examining patients with delayed motor milestones, progressive spasticity, gait difficulties, and neuromuscular weakness in the context of HSP. Eight novel variants in nine patients were described, clinically similar to the previously described disease phenotype associated with pathogenic variants. This study contributes to expanding the genetic spectrum of some rare subtypes of HSP.

22 Dec 2023·Genes

Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease.

Article

Author: Alba Escalera-Balsera ; Alberto M Parra-Perez ; Alvaro Gallego-Martinez ; Lidia Frejo ; Juan Martin-Lagos ; Victoria Rivero de Jesus ; Paz Pérez-Vázquez ; Patricia Perez-Carpena ; Jose A Lopez-Escamez

Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score > 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease.

News (Medical) associated with AP4M1

28 Sep 2023

·www.globenewswire.com

Trial participants with Spastic Paraplegia 50 (SPG50) and Charcot-Marie-Tooth disease type 4J (CMT4J) could benefit from this joint effort to manufacture new gene therapies that utilize adeno-associated virus serotype 9 (AAV9) to deliver corrected genesSAN DIEGO, Sept. 28, 2023 (GLOBE NEWSWIRE) -- Viralgen Vector Core (Viralgen) and Elpida Therapeutics (Elpida Tx) have partnered to manufacture gene therapies for use in clinical trials sponsored by Elpida Tx involving patients living with SPG50 or CMT4J. It is anticipated that these trials will take place at various sites in North America and Europe and will explore potential safety and efficacy of the new treatments to be manufactured, as well as potential quality of life improvements. SPG50 is a rare disease caused by mutations in the adaptor protein complex-4 mu 1 subunit (AP4M1), which is a protein responsible for intracellular vesicle trafficking, specifically the sorting and transport of membrane proteins within cells. The disease symptoms of children with SPG50 begin with low muscle tone, microcephaly (small head) and epilepsy, then progress to affect the entire body, resulting in intellectual disabilities and movement/neurological abnormalities. This rare disease is known to affect only around 90 people worldwide.1 Charcot-Marie-Tooth disease type 4J (CMT4J) is an autosomal recessive, potentially severe form of CMT disease caused by mutations of the lipid phosphatase FIG4, a protein involved in the regulation of phosphoinositide lipids and membrane trafficking within cells. The same CMT4J genotype can present symptoms ranging from mild clinical signs to severe disability.2 The partnership between Viralgen and Elpida Tx is expected to enable the efficient manufacture of the adeno-associated vector serotype 9 (AAV9) based therapies for use in Elpida Tx's anticipated multi-site clinical trials. Viralgen will manufacture these therapies using its production process with the Pro10TM cell line, which is exclusively licensed from AskBio and has been found to increase scalability, performance, and yield of AAV therapies.3 Terry Pirovolakis, Founder and CEO of Elpida Tx, remarks that "Viralgen is truly an amazing partner, demonstrating their genuine commitment to advance potential therapies for impacted patients. We feel so grateful and honored to be working with such an incredible partner." About Elpida Therapeutics Elpida Tx's mission aims to address the current significant unmet medical needs of patients with ultra-rare diseases. Through leveraging scientific advancements and the now well-established safety and understanding of certain gene therapies, Elpida Tx aims to put cures in reach of families and children who desperately and urgently need them. Elpida Tx's business model focuses on partnerships that promote efficiency and the chance to treat a greater number of patients, while being self-sustaining and replicable. Elpida Tx specifically focuses on advancing programs that traditional biotech companies find difficult to bring through to completion. The company pipeline includes programs that were deprioritized by biotech companies or that did not receive biotech investment to advance due to small patient populations, but which have excellent scientific data on which to build a program and springboard the science and opportunity. Elpida Tx plans to incorporate three more CNS programs into its initial program pipeline within the next six months through an application process designed for academic institutions and foundations. About Viralgen Vector CoreViralgen is a Contract Development and Manufacturing Organization (CDMO) founded in 2017 and exists as an independently operated subsidiary of AskBio, which is wholly owned and independently operated as a subsidiary of Bayer AG. As a manufacturer of Current Good Manufacturing Practice (cGMP) certified AAV, Viralgen offers the Pro10™ based suspension manufacturing platform, a technology licensed from AskBio and developed by Chief Technical Officer Josh Grieger, PhD, and Co-Founder R. Jude Samulski, PhD, at University of North Carolina. The Pro10™ platform has been found to increase scalability, performance, and yield of AAV therapies 3. Located in Spain, in the Gipuzkoa Science and Technology Park, Viralgen produces AAV gene therapy treatments for pharmaceutical and biotech companies with the aim of accelerating the delivery of new treatments that may improve patients' lives. The company's clinical facilities have four cGMP manufacturing suites, with 250-liter and 500-liter bioreactors. In 2020, Viralgen expanded within the Scientific Park by constructing a new building with three modules for large-scale commercial manufacturing. Each module of the state-of-the-art space includes three cGMP suites with a manufacturing capacity of >2,000 liters. The first module, which includes a suite dedicated to fully automated fill and finish operations, has received cGMP certification by the Spanish Agency for Medicines and Medical Devices (AEMPS) as part of the EMA network. For more information, visit viralgenvc.com. References:1 J Clin Invest. 2023 May 15; 133(10): e170226. 10.1172/JCI1702262 Brain. 2011 Jul; 134(7): 1959-1971. 10.1093/brain/awr1483 Mol Ther. 2016 Feb;24(2):287-297. doi: 10.1038/mt.2015.187. Epub 2015 Oct 6. For more information and interviews, please contact:Priscilla Assumpçãopriscilla@sg-branding.com This information is provided by Reach, the non-regulatory press release distribution service of RNS, part of the London Stock Exchange. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact rns@lseg.com or visit www.rns.com.

Gene TherapyClinical Study

28 Sep 2023

·www.biospace.com

Viralgen & Elpida Partner for SPG50 & CMT4J Trials

Viralgen Vector Core and Elpida Therapeutics partner to manufacture gene therapy medicines for anticipated Spastic Paraplegia 50 (SPG50) and Charcot-Marie-Tooth disease type 4J (CMT4J) clinical trials Trial participants with Spastic Paraplegia 50 (SPG50) and Charcot-Marie-Tooth disease type 4J (CMT4J) could benefit from this joint effort to manufacture new gene therapies that utilize adeno-associated virus serotype 9 (AAV9) to deliver corrected genes SAN SEBASTIAN, SPAIN / ACCESSWIRE / September 28, 2023 / Viralgen Vector Core (Viralgen) and Elpida Therapeutics (Elpida Tx) have partnered to manufacture gene therapies for use in clinical trials sponsored by Elpida Tx involving patients living with SPG50 or CMT4J. It is anticipated that these trials will take place at various sites in North America and Europe and will explore potential safety and efficacy of the new treatments to be manufactured, as well as potential quality of life improvements. SPG50 is a rare disease caused by mutations in the adaptor protein complex-4 mu 1 subunit (AP4M1), which is a protein responsible for intracellular vesicle trafficking, specifically the sorting and transport of membrane proteins within cells. The disease symptoms of children with SPG50 begin with low muscle tone, microcephaly (small head) and epilepsy, then progress to affect the entire body, resulting in intellectual disabilities and movement/neurological abnormalities. This rare disease is known to affect only around 90 people worldwide.1 Charcot-Marie-Tooth disease type 4J (CMT4J) is an autosomal recessive, potentially severe form of CMT disease caused by mutations of the lipid phosphatase FIG4, a protein involved in the regulation of phosphoinositide lipids and membrane trafficking within cells. The same CMT4J genotype can present symptoms ranging from mild clinical signs to severe disability.2 The partnership between Viralgen and Elpida Tx is expected to enable the efficient manufacture of the adeno-associated vector serotype 9 (AAV9) based therapies for use in Elpida Tx's anticipated multi-site clinical trials. Viralgen will manufacture these therapies using its production process with the Pro10TM cell line, which is exclusively licensed from AskBio and has been found to increase scalability, performance, and yield of AAV therapies.3 Terry Pirovolakis, Founder and CEO of Elpida Tx, remarks that "Viralgen is truly an amazing partner, demonstrating their genuine commitment to advance potential therapies for impacted patients. We feel so grateful and honored to be working with such an incredible partner." About Elpida Therapeutics Elpida Tx' s mission aims to address the current significant unmet medical needs of patients with ultra-rare diseases. Through leveraging scientific advancements and the now well-established safety and understanding of certain gene therapies, Elpida Tx aims to put cures in reach of families and children who desperately and urgently need them. Elpida Tx's business model focuses on partnerships that promote efficiency and the chance to treat a greater number of patients, while being self-sustaining and replicable. Elpida Tx specifically focuses on advancing programs that traditional biotech companies find difficult to bring through to completion. The company pipeline includes programs that were deprioritized by biotech companies or that did not receive biotech investment to advance due to small patient populations, but which have excellent scientific data on which to build a program and springboard the science and opportunity. Elpida Tx plans to incorporate three more CNS programs into its initial program pipeline within the next six months through an application process designed for academic institutions and foundations. About Viralgen Vector Core Viralgen is a Contract Development and Manufacturing Organization (CDMO) founded in 2017 and exists as an independently operated subsidiary of AskBio, which is wholly owned and independently operated as a subsidiary of Bayer AG. As a manufacturer of Current Good Manufacturing Practice (cGMP) certified AAV, Viralgen offers the Pro10™ based suspension manufacturing platform, a technology licensed from AskBio and developed by Chief Technical Officer Josh Grieger, PhD, and Co-Founder R. Jude Samulski, PhD, at University of North Carolina. The Pro10™ platform has been found to increase scalability, performance, and yield of AAV therapies 3. Located in Spain, in the Gipuzkoa Science and Technology Park, Viralgen produces AAV gene therapy treatments for pharmaceutical and biotech companies with the aim of accelerating the delivery of new treatments that may improve patients' lives. The company's clinical facilities have four cGMP manufacturing suites, with 250-liter and 500-liter bioreactors. In 2020, Viralgen expanded within the Scientific Park by constructing a new building with three modules for large-scale commercial manufacturing. Each module of the state-of-the-art space includes three cGMP suites with a manufacturing capacity of >2,000 liters. The first module, which includes a suite dedicated to fully automated fill and finish operations, has received cGMP certification by the Spanish Agency for Medicines and Medical Devices (AEMPS) as part of the EMA network. For more information, visit viralgenvc.com. References: 1 J Clin Invest. 2023 May 15; 133(10): e170226. 10.1172/JCI170226 2 Brain. 2011 Jul; 134(7): 1959-1971. 10.1093/brain/awr148 3 Mol Ther. 2016 Feb;24(2):287-297. doi: 10.1038/mt.2015.187. Epub 2015 Oct 6. For more information and interviews, please contact: Priscilla Assumpção priscilla@sg-branding.com This information is provided by Reach, the non-regulatory press release distribution service of RNS, part of the London Stock Exchange. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact rns@lseg.com or visit . SOURCE: Viralgen Vector Core View source version on accesswire.com:

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