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Lots of folks reaching out about the uniQure $QURE #AAV #GeneTherapy HOPE-B Ph3 trial for #HemophiliaB getting put on hold so I wanted to comment here on what we know, don't know, and need to know. 
Here is a press release, read this first: https://www.globenewswire.com/news-release/2020/12/21/2148517/0/en/uniQure-Announces-Clinical-Update-on-Hemophilia-B-Gene-Therapy-Program.html
First, we don't yet have enough info to know if this patient's #HepatocellularCarcinoma is related to AAV therapy or not. We've known for decades that #HCC is common in hemophiliacs. "Rate of HCC was at least 30 times higher than the background incidence" https://pubmed.ncbi.nlm.nih.gov/1650134/
We also know that hemophilia patients infected with hepatitis C virus (HCV) have a significantly increased risk of hepatocellular carcinoma from this complication. This patient had a history of both hepatitis C and B, & fatty liver, all complications.
https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-239-recommendations-on-screening-for-development-of-hepatocellular-cancer-in-patients-with-hepatitis-c
https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-239-recommendations-on-screening-for-development-of-hepatocellular-cancer-in-patients-with-hepatitis-c
What we don't know yet, and need to know, is the sequencing of the tumor. The patient is having surgery this week per @ProfMakris and presumably the tumor will be sent for whole genome sequencing and analysis. https://twitter.com/ProfMakris/status/1341062310299901953?s=20
Once we have the sequencing we can see if there has been an AAV integration event in an obvious problematic area like a proto-oncogene, tumor suppressor, etc. But it may not be that clear. There could be an integration but which is unrelated to HCC at all. This will take time.
If there were an integration in a non-obviously 'bad' spot in the genome we may need to model that in animals to know if it is causative. We can do this by targeting the AAV to integrate into a precise area of the genome like I and others have done here:
https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.23481
https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.23481
#AAV #Liver integrations in #Hemophilia has been seen in dogs as was reported in the beautiful paper from the lab of @DeniseSabatino2 at CHOP just last month. Follow Denise if you don't already, she's the real deal 
https://www.nature.com/articles/s41587-020-0741-7
https://www.nature.com/articles/s41587-020-0741-7
AAV liver integration and HCC have a dark and stormy relationship, unrelated to dark rum and ginger beer. This is a 
hotlydebated topic that can get you into a bar fight at ASGCT if you say the wrong thing in front of the wrong person. Bring brass knuckles if this is your jam.
hotlydebated topic that can get you into a bar fight at ASGCT if you say the wrong thing in front of the wrong person. Bring brass knuckles if this is your jam.
Here are some (not all) papers saying AAV doesn't lead to liver tumors, read them yourself and interpret for yourself:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069673/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923321/
https://pubmed.ncbi.nlm.nih.gov/23770691/
https://pubmed.ncbi.nlm.nih.gov/16043099/
https://pubmed.ncbi.nlm.nih.gov/16682254/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069673/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923321/
https://pubmed.ncbi.nlm.nih.gov/23770691/
https://pubmed.ncbi.nlm.nih.gov/16043099/
https://pubmed.ncbi.nlm.nih.gov/16682254/
Here are some (not all) papers saying AAV can/may/could/does lead to liver tumors, read them yourself and interpret for yourself:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655627/
https://www.nature.com/articles/ng.3389
https://www.nature.com/articles/ng.3893
https://pubmed.ncbi.nlm.nih.gov/11571571/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498805/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655627/
https://www.nature.com/articles/ng.3389
https://www.nature.com/articles/ng.3893
https://pubmed.ncbi.nlm.nih.gov/11571571/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498805/
Be aware, some of these papers are talking about wild-type AAV. Others use recombinant AAV we treat patients with. They are different. wtAAV has an integration hotspot at Chr 19q13.42 (aka AAVS1) in 1st exon of protein phosphatase 1 regulatory subunit 12C. Note: rAAV does not.
Another topic that has come up: Why would uniQure "risk" their trial by allowing #HemophiliaB patients with #HepC? HepC is very common among this patient population and later trials like Ph3's *should* be reflective of real patients, not perfect patients. I applaud uniQure here.
Summary: we don't know enough yet, lots of confounding factors going on, hold tight and let the scientists do their work. I encourage the team to submit the results to @ASGCTherapy for presentation at the 2021 mtg. I'm AAV Abstract Review Chair and am keen to see this presented.
