How can VLPs help deliver gene editing tools? Gene editing delivery video series (3/3)

Virus Like Particles (VLPs) are just what they sound like… they behave similar to a viral vector but they are inherently safer as they don’t deliver their cargo into a cell’s genome.
VLPs can bind to a target cell and deliver RNA and proteins into those cells.
Think of a VLP like a Lipid Nanoparticle that relies on the surface structure of a viral vector for cell binding and transduction. In terms of gene editing, guide RNA can be complexed with protein Cas9 and manufactured into a VLP. VLPs with pre-complexed guide RNA and Cas9 are currently being tested in animal models.
VLP features
VLPs promise the cell specific binding of lentiviral vectors, but without integration risks seen in LV or the cargo limiting AAV.
VLPs can be pseudotyped with different glycoproteins, enabling specific targeting of cell types of interest.
The future of VLP research…
Historically, we are already familiar with VLPs as they have been explored as a new vaccine platform. In order for VLPs to target a range of cells in the human body for gene editing, we will need to compliment the natural glycoproteins, possibly with cell specific antibodies. Various lab are tweaking with linkers and glycoproteins to optimize editing efficiency and cell tropism.
The Doudna lab uses the word EDVs to describe similar particles as VLPs
Sources:
Hamilton, Jennifer R., et al. "In vivo human T cell engineering with enveloped delivery vehicles." Nature Biotechnology (2024): 1-9.
Mohsen, Mona O., and Martin F. Bachmann. "Virus-like particle vaccinology, from bench to bedside." Cellular & molecular immunology 19.9 (2022): 993-1011.
An, Meirui, et al. "Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo." Nature biotechnology (2024): 1-12.

[@steveholmes1736]

Excellent presentation, very instructive. Thank you.

[@ogooluwaajayi4195]

As always, thanks for making this, Kevin! Great video, but you did seem to rush through this one a little bit. 😅 A question, please. I'm guessing Regeneron's recent successful in-vivo delivery via dual AAVs was publicised after you published the video, or you'd have mentioned it. Do you think this eliminates the size problem being a major obstacle to AAV usage? As for other topics, please consider making a video about what goes into the cost determination of cell and gene therapies. I understand the requirements of patient care especially due to ex-vivo delivery, but they just don't justify the enormous cost of, say, Casgevy in my opinion. Please consider making a video to provide better context. Thank you.

[@bridgepointbio]

Thanks for comment..... and you're right I haven't yet seen Regeneron's recent in vivo work. Appreciate the heads up, I will check that out.

[@bridgepointbio]

Good idea. I will plan on a video on the high cost of gene therapies.... In essence, it is sort of the wild west when it comes to drug pricing.... Drug development is highly regulated and transparent but drug pricing is mostly unregulated and opaque. The pharma company will analyze where they think they can get the highest net revenue without triggering substantial rejection from payors (private insurance or governments). That negotiation between pharma companies and payors will often be grounded in a health outcomes basis (QALYs, or cost effective equations) but ultimately, the pharma companies in multi payor nations can set the price at 'what the market will bear'. That mindset tends to keep moving prices up. We need more forces counter-acting that movement and pushing prices down. The US government is currently moving towards greater leverage and negotiating power for government insurance (Medicare/Medicaid). That may help. Other single payor nations can set the price they are willing to pay in a 'take it or leave it' stance. But - of course, ultimately, the pharma company can 'leave it' and walk away. We have seen that recently in Germany when they wouldn't pay the high price for Bluebird Bio's gene medicine for blood disorders. Bluebird wanted 1.8M, but Germany said they will only pay 950k. So, Bluebird left Europe.

[@bridgepointbio]

www.biopharmadive.com/news/bluebird-withdraw-gene-therapy-europe-skysona/608666/

[@ogooluwaajayi4195]

@@bridgepointbio oof. This looks more complicated than I imagined, but just as disappointing. Thanks for explaining.