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Mark Brimble

@brimble.bsky.social
215 followers 79 following 12 posts

Assistant Professor at WashU School of Medicine. AAV Gene therapy researcher + below average ultrarunner.

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Mark Brimble @brimble.bsky.social · 15/09/2026
We conclude that the high levels of Rep and Cap (0.5-1% of SMN transgene) are the due to packaging of these contaminants initiated at P5. This shows how key plasmid design is when producing viral vectors for drug delivery.
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Mark Brimble @brimble.bsky.social · 14/09/2026
New preprint! We identify the precise origin of DNA Rep/Cap contaminants previously observed in an AAV patient liver biopsy to be the result of an AAV P5 promoter placed directly after the AAV capsid gene in the manufacturing design. Great collaboration with UCL to build upon their prior findings.
medrxiv.org
P5 promoter-mediated incorporation explains REP/CAP manufacturing contaminants in patient liver after rAAV gene therapy
Sequencing of liver tissue from a patient treated with the rAAV gene therapy Zolgensma for spinal muscular atrophy recently revealed contaminating plasmid sequences derived from rAAV manufacturing wit...
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Asya Minervina @asya-minervina.bsky.social · 04/09/2026
Our paper is out! It turns out that finding the right TCR partner is a bit like matching socks🧦: almost every pair fits, but only a small fraction make the right match for antigen recognition. If you don’t feel like diving into the full paper, there’s also a one-page summary!
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Iva Zovkic @ivazovkic.bsky.social · 01/07/2026
Excited to share our latest #epigenetics and #memory manuscript published in @npp-journal.bsky.social We show that splice isoforms of histone macroH2A1 have distinct effects on memory and hippocampal gene regulation, especially memory suppressors. www.nature.com/articles/s41...
nature.com
Splice isoforms of the histone variant macroH2A1 differentially regulate hippocampal gene expression and memory formation - Neuropsychopharmacology
Neuropsychopharmacology - Splice isoforms of the histone variant macroH2A1 differentially regulate hippocampal gene expression and memory formation
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Mark Brimble @brimble.bsky.social · 05/05/2026
That's good! Vector builder has reliable production services for any transgene design but they can only service certain capsids.
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Mark Brimble @brimble.bsky.social · 04/05/2026
AAV transduction is pretty tricky in HSCs: the ITRs stimulate a DNA damage response and often result in CD34+ cell death - are you aiming for targeted TRAC site integration via AAV donor template? Shoot me a DM if interested I have a couple of ideas for how to get that done.
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Mark Brimble @brimble.bsky.social · 12/03/2026
This was such a fun collaboration, with an amazing outcome. We helped the Vetere lab use a triple AAV strategy to deliver an optogenetic circuit allowing for the precise detection of which neurons are responsible for the formation and recall of a memory. www.nature.com/articles/s41...
nature.com
Deconstruction of a memory engram reveals distinct ensembles recruited at learning - Nature Neuroscience
Pouget et al. identified distinct CA1 neuron ensembles active during specific moments of fear learning and uncovered the core engram essential for memory formation.
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Reposted by Mark Brimble
Gisella Vetere @gisellavetere.bsky.social · 11/03/2026
How does the brain build a memory? A common assumption is that the neurons activated during an experience collectively form the memory engram. In our new Nature Neuroscience paper (finally out!), we show that this is not the case. www.nature.com/articles/s41...
nature.com
Deconstruction of a memory engram reveals distinct ensembles recruited at learning - Nature Neuroscience
Pouget et al. identified distinct CA1 neuron ensembles active during specific moments of fear learning and uncovered the core engram essential for memory formation.
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Mark Brimble @brimble.bsky.social · 31/01/2026
Congratulations to now graduated PhD student Stephen Winston for leading this study on rAAV contaminants. This study shows that a mere 2 nucleotide modification to the (Rep78/68 driving) p5 promoter results in rAAV with equivalent titers but ~50-fold lower p5-derived contaminants. #genetherapy #AAV
cell.com
Rational engineering of the P5 TRS-mimic site and REP78/68 start codon yields promoter variants that improve rAAV vector purity while maintaining high titers.
During recombinant adeno-associated virus (rAAV) production, certain components of the manufacturing system can be encapsidated as unwanted nucleic acid contaminants. Prior work has established that t...
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Molecular Therapy Family of Journals @moltherapy.bsky.social · 28/01/2026
dlvr.it
Rational engineering of the P5 TRS-mimic site and REP78/68 start codon yields promoter variants that improve rAAV vector purity while maintaining high titers.
During recombinant adeno-associated virus (rAAV) production, certain components of the manufacturing system can be encapsidated as unwanted nucleic acid contaminants. Prior work has established that the p5 promoter is critical for efficient vector production and is responsible for a significant portion of this aberrant cross-packaging. The Rep binding element (RBE) and terminal resolution site (TRS)-mimic loop on p5 putatively facilitate off-target packaging of DNA directly adjacent to p5 into rAAV particles.
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Tomás Ryan @tjryan.bsky.social · 02/01/2026
Starting 2026 with a thread a very recent manuscripts at Ryan Lab @tcddublin.bsky.social @tbsi-tcd.bsky.social "Extinction and subsequent updating of innate fear responses to a visual looming stimulus rely on hippocampus-dependent mechanisms" journals.plos.org/plosbiology/... @PLOSBiology
journals.plos.org
Extinction and subsequent updating of innate fear responses to a visual looming stimulus rely on hippocampus-dependent mechanisms
How does the brain balance innate responses with adaptive learning when reacting to threats? This study shows that repeated exposure to looming stimuli reduces innate defensive responses via hippocamp...
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Reposted by Mark Brimble
Paul Thomas @pgtimmune.bsky.social · 24/11/2025
Two complementary studies from our group out today: a therapeutic peptide vaccine trial for fibrolamellar carcinoma (FLC) & TIRTL-Seq, our robust method for deep quantitative paired TCR sequencing a🧵w/ @markyarchoan.bsky.social & @pogorely.bsky.social www.nature.com/articles/s41...
nature.com
TIRTL-seq: deep, quantitative and affordable paired TCR repertoire sequencing - Nature Methods
TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.
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PLOS Biology @plosbiology.org · 29/09/2025
How do we balance innate responses & adaptive learning when reacting to threats? @tjryan.bsky.social &co show that repeated exposure to looming stimuli reduces innate defensive responses via #hippocampal modulation, revealing a vCA1 engram needed for learned #fear @plosbiology.org 🧪 plos.io/4pNSnNp
Patterns of c-Fos expression in the SC, PAG, and HPC reveal a loss of activity in the SC and PAG following extinction-updating but persistent activity of the vCA1. Top left: Engram labeling strategy. Bottom: TRAP2xAi32 mice underwent one of three types of behavioral paradigms; re-exposure (n = 6 mice) vs. no re-exposure (n = 6 mice), extinction (n = 7 mice) vs. innate (n = 8 mice), or updating (n = 11 mice) vs. innate (n = 8 mice). Mice were injected with 4-OHT to transiently induce c-Fos dependent EYFP upon first exposure to the looming stimulus, and later perfused 60 min following stimulus presentation at the end of the behavioral paradigm. Tolp right: Example histology from the SC, with an EYFP+c-Fos+ cell highlighted by the white arrow.
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Mark Brimble @brimble.bsky.social · 02/06/2025
So glad to see this story ready to share as a preprint. This was a really fun collaboration and a stunning finding with big potential implications. Congrats Iva!
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bioRxivpreprint @biorxivpreprint.bsky.social · 01/06/2025
Opposing effects of H2A.Z on memory, transcription and pathology in male and female Alzheimer's disease mice and patients www.biorxiv.org/content/10.1101/202…
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Mark Brimble @brimble.bsky.social · 27/03/2025
*You have a new citation, click here to view* Citing article: 'In contrast to a pointless 2024 study done by barely literate and grotesquely unattractive authors [12]'
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Mark Brimble @brimble.bsky.social · 05/03/2025
Had an excellent meeting with staff from @slotkin.senate.gov about the importance of supporting robust funding for Biomedical research. @immunologyaai.bsky.social and the community appreciate your support #PPFPHillDay
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bioRxiv Neuroscience @biorxiv-neursci.bsky.social · 29/12/2024
Plasticity of visual looming response reveals a dissociation of innate and learned components www.biorxiv.org/content/10.1101/202…
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Waggoner Lab @labwaggoner.bsky.social · 26/12/2024
Durable lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection @cp-immunity.bsky.social www.cell.com/immunity/ful...
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Mark Brimble @brimble.bsky.social · 13/12/2024
An amazing collaboration to be a part of: We helped @gisellavetere.bsky.social & @clementpouget.bsky.social simultaneously deliver 3 AAV constructs to Ca1 neurons. What they then acheived blew me away - the tagging of cells recruited in memory encoding with a temporal resolution of mere seconds!
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Paul Thomas @pgtimmune.bsky.social · 26/11/2024
We keep improving TIRTL-seq, see the updated preprint (www.biorxiv.org/content/10.1...)! New additions include: a manual 96-well protocol, code and raw data now available, and successful in vitro validation of EBV and SARS-CoV-2 TCRs.
biorxiv.org
TIRTL-seq: Deep, quantitative, and affordable paired TCR repertoire sequencing
α/β T cells are key players in adaptive immunity. The specificity of T cells is determined by the sequences of the hypervariable T cell receptor (TCR) α and β chains. Although bulk TCR sequencing offe...
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Reposted by Mark Brimble
Dr. Ina Klockner🧬👩‍🔬🔬 @inaklockner.bsky.social · 20/11/2024
New starter pack for all people interested in Gene Editing & Gene Therapy 🧬✂️ including Tools & Delivery|CRISPR-Cas|Zinc finger nucleases|Viral vectors|Non-viral delivery methods go.bsky.app/8R4dVez
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Mark Brimble @brimble.bsky.social · 25/09/2024
Glad to get the chance to write this commentary on a recent paper by Penaud Budloo et al that found miRNA contaminants within purified rAAV preparations. An interesting and unique AAV vector purity study
cell.com
Non-encapsidated miRNA contaminants found in AAV preparations
Adeno-associated virus (AAV) has been in clinical use for gene therapy applications for over a decade, with 6 FDA-approved drug products at the time of writing.1 However, this vector is manufactured i...
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Paul Thomas @pgtimmune.bsky.social · 23/09/2024
TCR repertoire dream: decoding immune status by sequencing TCRs. Problems: 1) Need paired TCRab 2) Interesting T cell clones are often VERY small. Our solution: TIRTL-seq 🐢Deep, quantitative, & affordable paired TCR repertoire sequencing🧵 www.biorxiv.org/content/10.1101/202…
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Mark Brimble @brimble.bsky.social · 22/02/2024
Not only is the alternative histone H2A.Z.1 involved in memory formation, this role is lysine acetylation dependent! Thrilled to have contributed to this great work from Iva Zovkic's lab
nature.com
Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification - Neuropsychopharmacology
Neuropsychopharmacology - Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification
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