Resolving Adeno-Associated Viral Particle Diversity With Charge Detection Mass Spectrometry

Pierson, Elizabeth E.; Keifer, David. Z.; Asokan, Aravind; Jarrold, Martin F.

doi:10.1021/acs.analchem.6b00883

Cited by 152Mass Spectrometry Techniques and ApplicationsVirus-based gene therapy researchAdvanced Proteomics Techniques and Applications

Resolving Adeno-Associated Viral Particle Diversity With Charge Detection Mass Spectrometry

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Pierson, Elizabeth E., Keifer, David. Z., Asokan, Aravind, Jarrold, Martin F.·2016·Analytical Chemistry

DOI 10.1021/acs.analchem.6b00883PMC PMC6537880

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Abstract

Recombinant adeno-associated viruses (AAVs) are promising vectors for human gene therapy. However, current methods for evaluating AAV particle populations and vector purity are inefficient and low resolution. Here, we show that charge detection mass spectrometry (CDMS) can resolve capsids that contain the entire vector genome from those that contain partial genomes and from empty capsids. Measurements were performed for both single-stranded and self-complementary genomes. The self-complementary AAV vector preparation appears to contain particles with partially truncated genomes averaging at half the genome length. Comparison to results from electron microscopy with manual particle counting shows that CDMS has no significant mass discrimination in the relevant mass range (after a correction for the ion velocity is taken into account). Empty AAV capsids are intrinsically heterogeneous, and capsids from different sources have slightly different masses. However, the average masses of both the empty and full capsids are in close agreement with expected values. Mass differences between the empty and full capsids for both single-stranded and self-complementary AAV vectors indicate that the genomes are largely packaged without counterions.

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CDMS is accurate and repeatable (<2% CV).
“The method is accurate and repeatable (<2% CV).”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [56]
CDMS resolves empty, partially filled, and full capsids and quantifies capsid content.
“Pierson and colleagues56 report successful resolution of empty, partially filled, and full capsids and quantification of capsid content using CDMS.”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [56]

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Anion-exchange HPLC assay for separation and quantification of empty and full capsids in multiple adeno-associated virus serotypes
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Single Particle Analyzer of Mass: A Charge Detection Mass Spectrometer with a Multi-Detector Electrostatic Ion Trap
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Approaches to Heterogeneity in Native Mass Spectrometry
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Direct Liquid Chromatography/Mass Spectrometry Analysis for Complete Characterization of Recombinant Adeno-Associated Virus Capsid Proteins
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Quantification of Empty, Partially Filled and Full Adeno-Associated Virus Vectors Using Mass Photometry
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Measurement of the accurate mass of a 50 MDa infectious virus
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Optimized Electrostatic Linear Ion Trap for Charge Detection Mass Spectrometry
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Charge Detection Mass Spectrometry Measurements of Exosomes and other Extracellular Particles Enriched from Bovine Milk
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Assessment of genome packaging in AAVs using Orbitrap-based charge-detection mass spectrometry
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Real-Time Analysis and Signal Optimization for Charge Detection Mass Spectrometry
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Cryo-electron Microscopy of Adeno-associated Virus
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Implementation of a Charge-Sensitive Amplifier without a Feedback Resistor for Charge Detection Mass Spectrometry Reduces Noise and Enables Detection of Individual Ions Carrying a Single Charge
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Stability and Dissociation of Adeno-Associated Viral Capsids by Variable Temperature-Charge Detection-Mass Spectrometry
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Analysis of thermally driven structural changes, genome release, disassembly, and aggregation of recombinant AAV by CDMS
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Purity and DNA content of AAV capsids assessed by analytical ultracentrifugation and orthogonal biophysical techniques
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Analysis of AAV-Extracted DNA by Charge Detection Mass Spectrometry Reveals Genome Truncations
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Separation of full and empty adeno-associated virus capsids by anion-exchange chromatography using choline-type salts
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Dynamic Calibration Enables High-Accuracy Charge Measurements on Individual Ions for Charge Detection Mass Spectrometry
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Multiple-Monitor HPLC Assays for Rapid Process Development, In-Process Monitoring, and Validation of AAV Production and Purification
Gagnon, P., Goričar, B., Mencin, N., Žvanut, T., Peljhan, S., Leskovec, M., & Štrancar, A. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13010113 · Cited by 41 · see citing works
Filling Adeno-Associated Virus Capsids: Estimating Success by Cryo-Electron Microscopy
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UniDecCD: Deconvolution of Charge Detection-Mass Spectrometry Data
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The downstream bioprocess toolbox for therapeutic viral vectors
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Challenges in downstream purification of gene therapy viral vectors
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Atmospheric Pressure Mass Spectrometry of Single Viruses and Nanoparticles by Nanoelectromechanical Systems
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Removal of empty capsids from adeno-associated virus preparations by multimodal metal affinity chromatography
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Single-Ion Mass Spectrometry for Heterogeneous and High Molecular Weight Samples
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Probing the Link among Genomic Cargo, Contact Mechanics, and Nanoindentation in Recombinant Adeno-Associated Virus 2
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Mass and charge distributions of amyloid fibers involved in neurodegenerative diseases: mapping heterogeneity and polymorphism
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Rapid Determination of Full and Empty Adeno-Associated Virus Capsid Ratio by Capillary Isoelectric Focusing
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Orbitrap-Based Mass and Charge Analysis of Single Molecules
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Resolution of Lipoprotein Subclasses by Charge Detection Mass Spectrometry
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Enhancement of recombinant adeno-associated virus activity by improved stoichiometry and homogeneity of capsid protein assembly
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Production and characterization of an AAV1-VP3-only capsid: An analytical benchmark standard
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Native Mass Spectrometry at the Convergence of Structural Biology and Compositional Proteomics
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Combining Surface-Induced Dissociation and Charge Detection Mass Spectrometry to Reveal the Native Topology of Heterogeneous Protein Complexes
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Determining Energies and Cross Sections of Individual Ions Using Higher-Order Harmonics in Fourier Transform Charge Detection Mass Spectrometry (FT-CDMS)
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Weighing synthetic polymers of ultra‐high molar mass and polymeric nanomaterials: What can we learn from charge detection mass spectrometry?
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Probing Antibody Binding to Canine Parvovirus with Charge Detection Mass Spectrometry
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Analytical methods to characterize recombinant adeno-associated virus vectors and the benefit of standardization and reference materials
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Size Exclusion Chromatography with Dual Wavelength Detection as a Sensitive and Accurate Method for Determining the Empty and Full Capsids of Recombinant Adeno-Associated Viral Vectors
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Dramatic Improvement in Sensitivity with Pulsed Mode Charge Detection Mass Spectrometry
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Development of a Two-Dimensional Liquid Chromatography-Mass Spectrometry Platform for Simultaneous Multi-Attribute Characterization of Adeno-Associated Viruses
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Charge detection mass spectrometry for the analysis of viruses and virus-like particles
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Mass spectrometry‐based methods to characterize highly heterogeneous biopharmaceuticals, vaccines, and nonbiological complex drugs at the intact‐mass level
Kaltashov, I. A., Ivanov, D. G., & Yang, Y. (2022) · Mass Spectrometry Reviews · doi:10.1002/mas.21829 · Cited by 24 · see citing works
Lot-to-Lot Variation in Adeno-Associated Virus Serotype 9 (AAV9) Preparations
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Disassembly Intermediates of the Brome Mosaic Virus Identified by Charge Detection Mass Spectrometry
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Analysis of Recombinant Adenovirus Vectors by Ion Trap Charge Detection Mass Spectrometry: Accurate Molecular Weight Measurements beyond 150 MDa
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Characterization of Virus Particles and Submicron-Sized Particulate Impurities in Recombinant Adeno-Associated Virus Drug Product
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Enhanced Multiplexing in Fourier Transform Charge Detection Mass Spectrometry by Decoupling Ion Frequency from Mass to Charge Ratio
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Adeno-associated Virus Virus-like Particle Characterization via Orthogonal Methods: Nanoelectrospray Differential Mobility Analysis, Asymmetric Flow Field-Flow Fractionation, and Atomic Force Microscopy
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Effects of Molecular Size on Resolution in Charge Detection Mass Spectrometry
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Mass spectrometry in gene therapy: Challenges and opportunities for AAV analysis
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Gene detection: An essential process to precision medicine
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A Native Mass Spectrometry-Based Assay for Rapid Assessment of the Empty:Full Capsid Ratio in Adeno-Associated Virus Gene Therapy Products
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Standardized workflow for multiplexed charge detection mass spectrometry on orbitrap analyzers
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Characterizing Heterogeneous Mixtures of Assembled States of the Tobacco Mosaic Virus Using Charge Detection Mass Spectrometry
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Application of Size Exclusion Chromatography with Multiangle Light Scattering in the Analytical Development of a Preclinical Stage Gene Therapy Program
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Analysis of Megadalton-Sized DNA by Charge Detection Mass Spectrometry: Entropic Trapping and Shearing in Nanoelectrospray
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Multimass Analysis of Adeno-Associated Virus Vectors by Orbitrap-Based Charge Detection Mass Spectrometry
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Weighing the DNA Content of Adeno-Associated Virus Vectors with Zeptogram Precision Using Nanomechanical Resonators
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Advances and opportunities in process analytical technologies for viral vector manufacturing
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Development and Validation of an Anion Exchange High-Performance Liquid Chromatography Method for Analysis of Empty Capsids and Capsids Encapsidating Genetic Material in a Purified Preparation of Recombinant Adeno-Associated Virus Serotype 5
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Antibody Binding to Recombinant Adeno Associated Virus Monitored by Charge Detection Mass Spectrometry
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Therapeutic Application and Structural Features of Adeno-Associated Virus Vector
Matsuzaka, Y., & Yashiro, R. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46080499 · Cited by 15 · see citing works
Molecular weight determination of adeno‐associate virus serotype 8 virus‐like particle either carrying or lacking genome via native nES gas‐phase electrophoretic molecular mobility analysis and nESI QRTOF mass spectrometry
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Surface Modified Nano-Electrospray Needles Improve Sensitivity for Native Mass Spectrometry
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Commentary: Multiplex dPCR and SV-AUC are Promising Assays to Robustly Monitor the Critical Quality Attribute of AAV Drug Product Integrity
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Accurately Mapping Image Charge and Calibrating Ion Velocity in Charge Detection Mass Spectrometry
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Comparison of three AUC techniques for the determination of the loading status and capsid titer of AAVs
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Partial genome content within rAAVs impacts performance in a cell assay-dependent manner
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Separation of full, empty, and partial adeno-associated virus capsids via anion-exchange chromatography with continuous recycling and accumulation
Lee, Y. S., Lee, J., Fang, K., Gee, G. V., Rogers, B. J., McNally, D., & Yoon, S. (2024) · Journal of Chromatography B · doi:10.1016/j.jchromb.2024.124206 · Cited by 12 · see citing works
Size-exclusion chromatography as a multi-attribute method for process and product characterization of adeno-associated virus
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Mass spectrometry friendly pH-gradient anion exchange chromatography for the separation of full and empty adeno-associated virus (AAV) capsids
Guapo, F., Füssl, F., Strasser, L., & Bones, J. (2023) · Analytical Methods · doi:10.1039/d3ay01560b · Cited by 11 · see citing works

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Prolonged Trapping of Adeno-Associated Virus Capsids Reveals that Genome Packaging Affects Single-Ion Mass Spectrometry Measurements
Ebberink, E. H. T. M., Yin, V. C., Deslignière, E., Barendregt, A., Wörner, T. P., Fort, K. L., Makarov, A., & Heck, A. J. R. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c13393 · Cited by 8 · see citing works
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Self-citation
Characterizing the content and structure of AAV capsids by size exclusion chromatography and charge detection mass-spectrometryPreprint
Pathak, K., Perrotti, G., Rosa, S., Robinett, G., Kasper, L., Xia, J., Escalante, C. R., & Gomes, F. P. (2025) · ChemRxiv · doi:10.26434/chemrxiv-2025-ddxpm
Characterizing the Content and Structure of AAV Capsids by Size Exclusion Chromatography and Orbitrap-Based Charge Detection-Mass Spectrometry
Pathak, K., Perrotti, G., Rosa, S. J., Robinett, G., Kasper, L., Xia, Q., Escalante, C. R., & Gomes, F. P. (2025) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.5c00074 · Cited by 11 · see citing works

Authors: Pierson, E. E., Keifer, D. Z., Asokan, A., & Jarrold, M. F.
Affiliations: Indiana University Bloomington (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Asokan, Aravind
Jarrold, Martin F.
ORCID: Pierson, Elizabeth E.
Keifer, David. Z.
Asokan, Aravind
Jarrold, Martin F.
Venue: Analytical Chemistry
Publisher: American Chemical Society (ACS)
Published: 2016-06-16
Volume: 88
Issue: 13
Pages: 6718-6725
ISSN: 0003-2700 (ISSN-L)
1520-6882
DOI: 10.1021/acs.analchem.6b00883
PMC: PMC6537880
OpenAlex: W2439361170
Cited by: 152
References: 59
Citations by year: 2026: 9 · 2025: 11 · 2024: 20 · 2023: 24 · 2022: 20 · 2021: 23 · 2020: 12 · 2019: 13 · 2018: 7 · 2017: 12 · 2016: 1
FWCI: 5.47
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Analytical Chemistry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Science Foundation (CHE-1531823)
U.S. Department of Health and Human Services (P01HL112761, R01HL089221)
Topics: Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords: adeno-associated virus, charge detection mass spectrometry, empty capsids, self-complementary AAV, genome packaging, gene therapy vectors
MeSH terms: Dependovirus, Capsid, DNA, Viral, Genetic Vectors, Microscopy, Electron, Mass Spectrometry, Capsid Proteins

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Resolving Adeno-Associated Viral Particle Diversity With Charge Detection Mass Spectrometry

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