Review
Cell Biology
Mateus Grings, Moacir Wajner, Guilhian Leipnitz
Summary: Ethylmalonic encephalopathy is a severe intoxication disorder caused by mutations in the ETHE1 gene. Disruption of mitochondrial and redox homeostasis, as well as oxidative stress, are important pathomechanisms in tissue damage. Current treatment does not effectively prevent encephalopathy.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2022)
Article
Microbiology
Edward E. Large, Michael S. Chapman
Summary: Adeno-associated viruses (AAV) are widely used for gene therapy, and monoclonal antibodies against various AAV serotypes have been developed. Previous studies suggested that neutralizing antibodies inhibit binding to glycan receptors or interfere with post-entry steps. However, recent research has identified a protein receptor and revealed that antibody interference with protein receptor binding may be the predominant mechanism of neutralization.
FRONTIERS IN MICROBIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Leyao Li, Lakshmy Vasan, Bryan Kartono, Kevan Clifford, Ahmadreza Attarpour, Raghav Sharma, Matthew Mandrozos, Ain Kim, Wenda Zhao, Ari Belotserkovsky, Claire Verkuyl, Gerold Schmitt-Ulms
Summary: This review introduces the use of recombinant adeno-associated virus (rAAV) vectors in the treatment of neurodegenerative diseases, highlighting recent research advancements and challenges. It provides a reference for newcomers to the field and directs researchers struggling to keep up with the literature towards important studies. The review covers early milestones, current clinical trials, gene editing applications, and payload elements of rAAV vectors, as well as discusses the risks and mitigation strategies associated with off-target effects and immunogenicity.
Review
Neurosciences
Jing Wang, Mengna Zhu, Jingyi Sun, Lina Feng, Mingfeng Yang, Baoliang Sun, Leilei Mao
Summary: Stroke is associated with devastating clinical outcomes, and current treatment strategies are largely ineffective. Gene therapy using adeno-associated viruses (AAVs) as gene vectors has emerged as a promising approach for treating central nervous system diseases. This review provides an overview of the biological characteristics of AAV vectors and therapeutic advancements in preclinical models of ischemic stroke. It further investigates the potential of manipulating AAV vectors in preclinical applications, emphasizing the challenges and prospects in viral vector selection, drug delivery strategies, immune reactions, and clinical translation.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Review
Biotechnology & Applied Microbiology
Sha Sha, Andrew J. Maloney, Georgios Katsikis, Tam N. T. Nguyen, Caleb Neufeld, Jacqueline Wolfrum, Paul W. Barone, Stacy L. Springs, Scott R. Manalis, Anthony J. Sinskey, Richard D. Braatz
Summary: The article focuses on analyzing the bottlenecks in rAAV production during cell culture, comparing differences between wild-type and recombinant systems, and proposing future directions for improvement.
BIOTECHNOLOGY ADVANCES
(2021)
Article
Pharmacology & Pharmacy
Yu (Zoe) Zhang, Roberto A. DePaz, Jared S. Bee, Tristan Marshall
Summary: The study developed a lyophilized AAV formulation that maintained stability for 24 months, showcasing the feasibility of a dried formulation for AAV gene therapy. By optimizing the composition and residual moisture range, as well as utilizing sucrose, citrate, and glycerol, AAV8 was protected from degradation and potency loss.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Engineering, Chemical
Abhiram Arunkumar, Nripen Singh
Summary: This study quantitatively investigated the ultrafiltration behavior of AAVs using different membrane molecular weight cut-off and operating conditions, showing that these factors can impact the flux and transmission of AAV. The study found that a 100 kDa ultrafiltration membrane can act as a completely retentive membrane or as significantly permeable to AAV serotypes depending on the operating conditions.
JOURNAL OF MEMBRANE SCIENCE
(2021)
Article
Clinical Neurology
Amanda L. Gross, Heather L. Gray-Edwards, Cassie N. Bebout, Nathan L. Ta, Kayly Nielsen, Brandon L. Brunson, Kalajan R. Lopez Mercado, Devin E. Osterhoudt, Ana Rita Batista, Stacy Maitland, Thomas N. Seyfried, Miguel Sena-Esteves, Douglas R. Martin
Summary: Researchers have found that intravenous administration of AAV9 vector can effectively treat GM1 gangliosidosis, increasing the lifespan of animals and improving their quality of life and neurological function. After treatment, neurological abnormalities were mild, CSF biomarkers were normalized, and urinary glycosaminoglycans decreased to normal levels.
Article
Cell Biology
Gijung Kwak, Olesia Gololobova, Neeraj Sharma, Colin Caine, Marina Mazur, Kathleen Mulka, Natalie E. West, George M. Solomon, Garry R. Cutting, Kenneth W. Witwer, Steven M. Rowe, Michael Paulaitis, George Aslanidi, Jung Soo Suk
Summary: Clinical implementation of inhaled gene therapy using adeno-associated virus (AAV) vector has been challenging due to difficulty in transducing lung airway cells. However, by combining AAV serotype 6 (AAV6) with extracellular vesicles (EVs), researchers have discovered a method that greatly enhances gene expression in respiratory cells, offering a safe and effective treatment strategy.
JOURNAL OF EXTRACELLULAR VESICLES
(2023)
Article
Virology
L. Patrick Havlik, Anshuman Das, Mario Mietzsch, Daniel K. Oh, Jonathan Ark, Robert McKenna, Mavis Agbandje-McKenna, Aravind Asokan
Summary: New AAV variants with enhanced cellular binding, uptake, and transduction have been evolved through infectious cycling, with one able to recognize sulfated glycosaminoglycans and another switching receptors from AAVR to integrin beta 1. The visualization of the AAVhum.8 capsid revealed a newly acquired integrin recognition motif, providing insights into designing viruses with improved attributes for gene therapy applications.
JOURNAL OF VIROLOGY
(2021)
Article
Virology
Sean M. Crosson, Antonette Bennett, Diego Fajardo, James J. Peterson, Hangning Zhang, Wei Li, Matthew T. Leahy, Colin K. Jennings, Ryan F. Boyd, Sanford L. Boye, Mavis Agbandje-McKenna, Shannon E. Boye
Summary: Rationally designed AAV2-based capsid variants with specific hydrophilic and hydrophobic amino acid mutations can significantly enhance retinal transduction, especially when considering the impact of these mutations on HSPG binding and vector tropism in a clinically relevant animal model.
JOURNAL OF VIROLOGY
(2021)
Article
Virology
Anshuman Das, Madhuvanthi Vijayan, Eric M. Walton, V. Grace Stafford, David N. Fiflis, Aravind Asokan
Summary: This study provides evidence that the double-stranded DNA binding protein NP220, in association with the human silencing hub (HUSH) complex, mediates transcriptional silencing of single-stranded as well as self-comple- mentary rAAV genomes. The AAV capsid appears to play an important role in NP220-mediated silencing of packaged genomes. Modulation of epigenetic pathways could potentially improve rAAV expression.
JOURNAL OF VIROLOGY
(2022)
Article
Pharmacology & Pharmacy
Yuechuan Xu, Bowen Jiang, Poulami Samai, Sven-Moller Tank, Mohammed Shameem, Dingjiang Liu
Summary: This study characterized the impact of freeze-thaw cycles on AAV8 and found that it resulted in an increase in free single-stranded DNA (ssDNA) leaked from AAV8. Next Generation Sequencing revealed that the leaked ssDNA primarily consisted of genome DNA. Similar behavior was observed in different serotypes of AAV. Furthermore, formulation screening showed that the addition of 10% sucrose and 0.1% poloxamer 188 could reduce ssDNA leakage in AAV samples after freeze-thaw cycles.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Article
Multidisciplinary Sciences
Zachary C. Elmore, L. Patrick Havlik, Daniel K. Oh, Leif Anderson, George Daaboul, Garth W. Devlin, Heather A. Vincent, Aravind Asokan
Summary: The membrane-associated accessory protein (MAAP) is identified as a novel viral egress factor that promotes the secretion of AAV serotypes. MAAP contains a cationic amphipathic domain critical for AAV secretion. Restoring MAAP expression can rescue the secretion defect in various AAV serotypes with mutated start sites.
NATURE COMMUNICATIONS
(2021)
Article
Biochemical Research Methods
Logan Thrasher Collins, Selvarangan Ponnazhagan, David T. Curiel
Summary: Gene therapy has the potential to revolutionize disease treatment through direct genetic manipulation of cells. However, the high cost of Adeno-associated virus (AAV) gene therapy limits its accessibility, making it unaffordable for most patients. Therefore, efforts to decrease the production cost of AAVs using synthetic biology design have been proposed to make gene therapy more widely available.
ACS SYNTHETIC BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Massimo Zeviani, Valerio Carelli
Summary: The retina is a vulnerable target for defects in oxidative phosphorylation (OXPHOS) due to mitochondrial impairment, resulting in conditions such as retinal dystrophy and optic atrophy. Mutations in mitochondrial DNA (mtDNA) and nuclear genes are implicated in mitochondrial retinopathies, presenting as isolated diseases or part of more complex syndromes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Massimo Zeviani, Carlo Viscomi
Summary: Mitochondria are vital organelles responsible for generating energy in cells. Mutations in mtDNA or nuclear genes can lead to complex neurological disorders. Understanding these diseases is essential for the field of mitochondrial medicine due to the diverse genetic and phenotypic heterogeneity.
Article
Cell Biology
Paolo Santambrogio, Maddalena Ripamonti, Anna Cozzi, Marzia Raimondi, Chiara Cavestro, Ivano Di Meo, Alicia Rubio, Stefano Taverna, Valeria Tiranti, Sonia Levi
Summary: This study established a specific newly generated astrocyte model that can recapitulate the human phenotype associated with neurodegeneration associated with defective pantothenate kinase-2. It provides insights into the pathogenetic mechanisms underlying the disease.
CELL DEATH & DISEASE
(2022)
Article
Multidisciplinary Sciences
Patrizia Tornabene, Rita Ferla, Manel Llado-Santaeularia, Miriam Centrulo, Margherita Dell'Anno, Federica Esposito, Elena Marrocco, Emanuela Pone, Renato Minopoli, Carolina Iodice, Edoardo Nusco, Settimio Rossi, Hristiana Lyubenova, Anna Manfredi, Lucio Di Filippo, Antonella Iuliano, Annalaura Torella, Giulio Piluso, Francesco Musacchia, Enrico Maria Surace, Davide Cacchiarelli, Vincenzo Nigro, Alberto Auricchio
Summary: The study introduces a novel gene therapy approach, AAV-HITI, to overcome challenges in gene therapy. The results show that AAV-HITI enables efficient gene integration in both retina and liver, leading to therapeutic benefits for genetic diseases.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Andrea Cavaliere, Silvia Marchet, Ivano Di Meo, Valeria Tiranti
Summary: This paper presents a detailed protocol for generating, selecting, and characterizing transmitochondrial cybrids, which is of great significance for validating the pathogenicity of mutations and studying their biochemical impact.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2022)
Editorial Material
Biochemistry & Molecular Biology
Carlo Viscomi, Maria Eugenia Soriano
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Maddalena Ripamonti, Paolo Santambrogio, Gabriella Racchetti, Anna Cozzi, Ivano Di Meo, Valeria Tiranti, Sonia Levi
Summary: PKAN disease is caused by mutations in the PANK2 gene, leading to excessive iron deposition in the brain and progressive neurodegeneration. The pathogenic mechanisms of PKAN are still unclear, and current therapies only alleviate symptoms. CoA biosynthesis impairment may disrupt crucial intracellular mechanisms involved in membrane fusions and vesicular trafficking, resulting in aberrant transferrin receptor-mediated iron uptake.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Cell Biology
Alberto Danese, Simone Patergnani, Alessandra Maresca, Camille Peron, Andrea Raimondi, Leonardo Caporali, Saverio Marchi, Chiara La Morgia, Valentina Del Dotto, Claudia Zanna, Angelo Iannielli, Alice Segnali, Ivano Di Meo, Andrea Cavaliere, Magdalena Lebiedzinska-Arciszewska, Mariusz R. Wieckowski, Andrea Martinuzzi, Milton N. Moraes-Filho, Solange R. Salomao, Adriana Berezovsky, Rubens Belfort, Christopher Buser, Fred N. Ross-Cisneros, Alfredo A. Sadun, Carlo Tacchetti, Vania Broccoli, Carlotta Giorgi, Valeria Tiranti, Valerio Carelli, Paolo Pinton
Summary: Patients with Leber's hereditary optic neuropathy (LHON) exhibit sustained abnormal autophagy and compartment-specific mitophagy activity, disrupting mitochondrial homeostasis and leading to defective bioenergetics and excessive reactive oxygen species production. Modulating autophagy and mitochondrial biogenesis can counteract this pathological mechanism.
Review
Pharmacology & Pharmacy
Alessia Di Donfrancesco, Giulia Massaro, Ivano Di Meo, Valeria Tiranti, Emanuela Bottani, Dario Brunetti
Summary: This article provides a comprehensive overview of the application of gene therapy in mitochondrial diseases (MDs), addressing the main challenges, feasible solutions, and future prospects.
Review
Biochemistry & Molecular Biology
Marco D'Amato, Francesca Morra, Ivano Di Meo, Valeria Tiranti
Summary: Mitochondrial diseases are genetic conditions caused by mutations in nuclear or mitochondrial DNA. Existing therapies are insufficient for treating the wide range of mtDNA mutations. Mitochondrial transplantation offers a potential solution by transferring healthy mitochondria to dysfunctional cells or tissues. This review explores the mechanisms and methods of intercellular mitochondrial transfer and discusses its potential therapeutic applications. Mitochondrial transplantation could induce a shift in heteroplasmy and potentially attenuate or prevent pathological phenotypes. However, further research is needed before its widespread use in mitochondrial medicine.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Paolo Santambrogio, Anna Cozzi, Ivano Di Meo, Chiara Cavestro, Cristina Vergara, Laura Rodriguez-Pascau, Marc Martinell, Pilar Pizcueta, Valeria Tiranti, Sonia Levi
Summary: This study tested the effectiveness of the brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone in ameliorating mitochondrial defects in a cellular model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). The results showed that leriglitazone improved the viability and respiratory activity of PKAN cells, while reducing iron accumulation, suggesting it could be a beneficial therapeutic approach for PKAN treatment.
Article
Pharmacology & Pharmacy
Enrica Zanuttigh, Kevork Derderian, Miriam A. Guera, Arie Geerlof, Ivano Di Meo, Chiara Cavestro, Stefan Hempfling, Stephanie Ortiz-Collazos, Mario Mauthe, Tomasz Kmiec, Eugenia Cammarota, Maria Carla Panzeri, Thomas Klopstock, Michael Sattler, Juliane Winkelmann, Ana C. Messias, Arcangela Iuso
Summary: "Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a neurodegenerative disorder caused by mutations in the C19orf12 gene. This study found that there were no consistent alterations in mitochondrial functions or cellular signaling in MPAN fibroblasts, but autophagy initiation was consistently impaired. Furthermore, several potential therapeutic compounds for MPAN were identified through screening autophagy modulators."
Review
Biochemistry & Molecular Biology
Chiara Cavestro, Daria Diodato, Valeria Tiranti, Ivano Di Meo
Summary: Coenzyme A (CoA) is an essential cofactor that plays a vital role in numerous enzymatic reactions and cellular processes. Four rare human inborn errors of CoA biosynthesis have been described, all stemming from variants in genes encoding enzymes involved in the same metabolic process. This review provides an overview of CoA metabolism and functions, and summarizes the current knowledge on disorders associated with its biosynthesis, including proposed pathomechanisms and potential therapeutic approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
Flavia Palombo, Camille Peron, Leonardo Caporali, Angelo Iannielli, Alessandra Maresca, Ivano Di Meo, Claudio Fiorini, Alice Segnali, Tiina Manninen, Francesca L. Sciacca, Ambra Rizzo, Sonia Levi, Anu Suomalainen, Alessandro Prigione, Vania Broccoli, Valerio Carelli, Valeria Tiranti
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)