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Seth Cheetham

@sethcheetham.bsky.social

1K followers 180 following 51 posts

mRNA drug discovery | Deputy-Director BASE mRNA Facility | Associate Professor at the University of Queensland.

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Seth Cheetham @sethcheetham.bsky.social · Nov 18

The greatest challenge for #mRNA-LNP therapies is targeting non-liver tissues. To overcome this, we developed customisable bispecific antibodies to tether mRNA-LNPs to cell-surface proteins, achieving efficient and selective mRNA delivery in vivo. Preprint 👇

t.co/0nJj8eVsqC

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Seth Cheetham @sethcheetham.bsky.social · Jun 10

To accelerate #mRNA vaccine and therapy research, we're excited to share our end-to-end protocol for mRNA design, synthesis and encapsulation in @natprot.nature.com.

Protocol development led by @laura-leighton.bsky.social, Natasha Chaudhary and Tim [email protected]

rdcu.be/eqiF1

The design, manufacture and LNP formulation of mRNA for research use

Nature Protocols - This protocol describes simple, small-scale laboratory production of mRNA for research and preclinical use. This includes sequence design, DNA template production, mRNA synthesis...

rdcu.be

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Seth Cheetham @sethcheetham.bsky.social · May 16

Today, a huge milestone for personalised #mRNA therapeutics for inherited disease! A baby with an ultra-rare mitochondrial metabolic disease was treated at UPenn with an mRNA-encoded gene-corrector. The mRNA was made to treat a single individual in just 7 months!

www.nejm.org/doi/full/10....

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Seth Cheetham @sethcheetham.bsky.social · Apr 2

Crucially, this approach doesn't require a new LNP, it works with FDA-approved formulations. We hope that this approach will enable targeted mRNA therapeutics for diverse diseases. Work led by Bettina Dietmair, James Humphries and Chris Howard. @basemrna.bsky.social

Seth Cheetham @sethcheetham.bsky.social · Apr 2

The technology is programmable and works with other targeting arms including anti-PSMA (highly expressed on prostate cancer cells) bispecifics. 6/

Seth Cheetham @sethcheetham.bsky.social · Apr 2

Bispecifics can be used by combining with the mRNA-LNP (pre-mixing) or the bispecific can be administered first (pre-targeting). 5/

Seth Cheetham @sethcheetham.bsky.social · Apr 2

As proof of concept we used anti-EGFR bispecifics to deliver mRNA to mouse breast cancer xenografts. The mRNA-payload (luciferase) is very efficiently delivered in vivo. 4/

Seth Cheetham @sethcheetham.bsky.social · Apr 2

To overcome this obstacle we developed bispecific antibodies that bind to PEG on the surface of LNPs and to cell-surface markers. 3/

Seth Cheetham @sethcheetham.bsky.social · Apr 2

Getting a high dose of mRNA to target tissues is one of the toughest problems for broad use of mRNA-LNP therapies. When administered systemically mRNA-LNPs go the liver with little delivery to other tissues. 2/

Seth Cheetham @sethcheetham.bsky.social · Apr 2

Systemic mRNA-LNP delivery beyond the liver? Check out our recent paper demonstrating cell-specific mRNA-LNP delivery using PEG- and target cell-specific antibodies. This approach can customised to any target cell-type with off-the-shelf mRNA-LNPs. 1/
sciencedirect.com/science/arti...

Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell surface markers

Efficient delivery of mRNA-lipid nanoparticles (LNPs) to specific cell types remains a major challenge for mRNA therapeutics. Conventional targeting a…

sciencedirect.com

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Seth Cheetham @sethcheetham.bsky.social · Mar 20

Exited to share our latest preprint! mRNA-LNPs are efficiently delivered to healthy livers, but what about liver tumours? Our postdoc @laura-leighton.bsky.social found liver tumours efficiently take up mRNA, enabling next generation mRNA-LNP cancer therapeutics.

www.biorxiv.org/content/10.1...

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Reposted by Seth Cheetham

Richard Behringer @rrbehringer.bsky.social · Mar 12

Developmental biology research leads to fundamental discoveries for biomedical research. RNA Vaccines. Lane et al., 1971 PMID: 5169490. Images by Brandy Walker & Amaya Moss @rkmille . @socdevbio.bsky.social 3/12

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Seth Cheetham @sethcheetham.bsky.social · Mar 6

Happy to sure our protocol if helpful, just send me a DM

Seth Cheetham @sethcheetham.bsky.social · Mar 6

We use q5 which has a very low error rate. We've done a lot of ONTseq of plasmid and pcr templates and don't see any increase in error rate, but we see way better polyA integrity.

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Seth Cheetham @sethcheetham.bsky.social · Mar 6

How much mRNA are you producing? We routinely use PCR to generate templates for up to 1-20mg productions. I know people that have done larger batches too.

Seth Cheetham @sethcheetham.bsky.social · Mar 6

There are some tweaks like segmented polyA tails that somewhat reduce deletions, but they're still very frequent. Worse, they are sometimes subclonal so sanger sequencing doesn't even detect the deletion. The field definitely needs better synthetic biology solutions.
doi.org/10.1261/rna....

Segmented poly(A) tails significantly reduce recombination of plasmid DNA without affecting mRNA translation efficiency or half-life

A monthly journal publishing high-quality, peer-reviewed research on all topics related to RNA and its metabolism in all organisms

doi.org

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Reposted by Seth Cheetham

Christine Mordstein @cmordstein.bsky.social · Mar 5

Calling on #ONT #Nanopore #sequencing experts: when sequencing through a stretch of 120nt dA using a DNA plasmid kit (outsourced in our case), what should one expect as average length in the output? The loss we are seeing is a bit extreme #RNAsky

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Seth Cheetham @sethcheetham.bsky.social · Mar 6

Could be real though, polyA deletions in plasmids are really common and one of the reasons we switched to PCR-based templates.

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Seth Cheetham @sethcheetham.bsky.social · Mar 6

#mRNA meets Tardigrades! Delivery of an mRNA encoding a protein from the famously tough animal can protect healthy tissue from damaging radiation. Very creative! #RNAsky

www.nature.com/articles/s41...

Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades - Nature Biomedical Engineering

Radiation-therapy-induced DNA damage in oral and rectal epithelial cells can be reduced via the nanoparticle-mediated local delivery of messenger RNA encoding for a damage-suppressor protein found in ...

www.nature.com

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Seth Cheetham @sethcheetham.bsky.social · Mar 6

@helengunter-mrna.bsky.social is the expert at this.

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Seth Cheetham @sethcheetham.bsky.social · Mar 2

Not the best weather forecast for Brisbane 😬

Seth Cheetham @sethcheetham.bsky.social · Feb 26

Preach!

Seth Cheetham @sethcheetham.bsky.social · Jan 31

You might be a bit overqualified Scott ;)

Seth Cheetham @sethcheetham.bsky.social · Jan 31

Interested in undertaking a PhD in the transformative field #mRNA cancer vaccines? I have an earmarked #PhD scholarship available for an outstanding domestic student to join our team at UQ and @basemrna.bsky.social. If this sounds like you, get in touch.

study.uq.edu.au/study-option...

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Seth Cheetham @sethcheetham.bsky.social · Jan 29

New #mRNA cap structures get you more bang (protein) for your buck! Nice new research from @jmcoller.bsky.social in collaboration with Trilink shows the CleanCap M6 analogue inhibits decapping and substantially increases protein expression in vivo.

www.cell.com/molecular-th...

CleanCap M6 inhibits decapping of exogenously delivered IVT mRNA

In this manuscript, Mandell and colleagues present CleanCap M6, a next generation 5’ cap analog that outperforms existing industry standards in live mice. Mandell and colleagues found that this cap ex...

www.cell.com

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Seth Cheetham @sethcheetham.bsky.social · Jan 20

Wow this is super cool! Single-cell resolution imaging of #mRNA-LNP biodistribution in cleared mouse bodies.

www.nature.com/articles/s41...

Nanocarrier imaging at single-cell resolution across entire mouse bodies with deep learning - Nature Biotechnology

An integrated experimental and deep learning pipeline reveals cell-level targeting of nanocarriers in whole bodies.

www.nature.com

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