Karlo Perica

Physician and scientist focused on developing new cell therapies for cancer.

[Karlo Perica @PericaKarlo]

Our research group focuses on making effective, affordable, and widely accessible cell therapies for cancer using in vivo gene editing and allogeneic cell therapies. @ASGCTherapy @ASCO @ASH_hematology @sitcancer @CancerResearch

[Thomas Norman @thenormanlab]

1/ Most genes and variants matter somewhere but look silent in any one cell model. Can we build conditions that reveal phenotypes? With @kanishkadey, we engineer cell states to expose hidden disease biology and trace how genetic risk reaches disease genes. https://t.co/pUHPPjxTkX

[Bowen LI @BowenLi_Lab]

🧬 Excited to share our new work in @NatureBiotech!
Paper: https://t.co/7bc59q8p7O Research Briefing: https://t.co/o5wKM3RQBr
Large gene editors require large mRNAs, but LNPs are typically discovered using much smaller reporter RNAs. We asked: does RNA size matter when discovering delivery lipids?

Using a large base-editor mRNA for high-throughput screening, we identified LC-1, an ionizable lipid that enabled efficient gene editing in the liver, lung, and brain via different administration routes in mice, with up to 4× higher Cas9 editing than benchmark LNPs. LC-1 also efficiently delivered base editors for disease-relevant targets in hypercholesterolemia, cystic fibrosis, and Angelman syndrome.

Why does LC-1 work so well? Cryo-EM and X-ray scattering revealed that LC-1 LNPs form an ordered, inverted-hexagonal structure that persists with large RNA cargo. This membrane-fusing structure helps RNA escape from endosomes, the compartments that can trap it inside cells. In cell studies, LC-1 released roughly twice as much large mRNA into the cytosol as the benchmark formulations. We show that LC-1's key design features also apply to ionizable lipids made through other synthetic routes.

These findings show that accounting for RNA size from the start can change which lipids we discover and improve delivery of large gene editors. This could help expand the delivery options available for future gene-editing medicines.

Thank you to all our co-authors, collaborators and funders @CIHR_IRSC @NSERC_CRSNG @UofTPharmacy @LisaDolovich @PMResearch_UHN @bradwouters #LipidNanoparticles #GeneEditing #RNATherapeutics

[Journal for ImmunoTherapy of Cancer @jitcancer]

New #JITC article: "Gene regulatory elements determine efficacy of BCMA-targeted CAR-T cell products" https://t.co/QPjbPVYJMW

[Lowe Lab @LoweLabMSKCC]

Excited to share our new paper, out today in @ScienceMagazine! We developed senescence-modulating nanoparticles (SMNPs) that target P-selectin+ pathogenic senescent-like macrophages in fibrotic tissues and tumors.
https://t.co/S1Sjfci2Yj

[Karlo Perica @PericaKarlo]

The EF1a promoter is the most popular choice for driving lentiviral CARs, so this is a story of unique issues with ide-cel.
And indeed we would predict that many of the forthcoming investigational BCMA CARs, which use EF1a, will behave more like cilta-cel than ide-cel.

[Karlo Perica @PericaKarlo]

Now online @NatureComms, our manuscript describing why the myeloma CAR T cell cilta-cel is more effective than a very similar CAR, ide-cel.

Led by the very talented Kevin Herrera and Sneha Mitra, and in collaboration with the Leslie Laboratory.
@MSKCancerCenter @szusmani

[Karlo Perica @PericaKarlo]

Furthermore, and quite surprisingly, cilta-cels unique dual-nanobody binder design made only a limited contribution to either driving this state or overall efficacy in animal models.
Instead, the EF1a promoter, rather than ide-cels MND promoter, explains the difference.

[Karlo Perica @PericaKarlo]

Congratulations @CalebLareau and team! Very cool binder engineering approach.

[Caleb Lareau @CalebLareau]

Three years ago, my lab at @MSKCancerCenter set out to see if we could harness AI for new therapeutic proteins.

Today in @natBME, our first step in developing these AI-designed molecules as anti-tumor therapies is online.

Read more here: 1/n https://t.co/eb2ufazEKC

[Karlo Perica @PericaKarlo]

Joining twitter to share recent and upcoming work from the Perica laboratory at MSKCC. @MSKCancerCenter @szusmani