Gene therapy for Hemophilia A

So what do you do after you use a genetically modified virus to treat-->functionally cure Hemophilia B?

Why, use a genetically modified virus to treat-->hopefully functionally cure Hemophilia A, of course!

Generation of an optimized lentiviral vector encoding a high-expression factor VIII transgene for gene therapy of hemophilia A

Though they are both 'hemophilia', hemophilia A and B are different creatures.  Likewise, the way virologists are going about treating these two illnesses are different.

Hemophilia B is when someone (usually a male) has mutations in their clotting Factor IX gene.  Scientists have cured/grossly reduced the number of necessary treatments hemophilia B patients require by using an adenovirus to deliver a functional copy of Factor IX.

Hemophilia A is when someone (usually a male) has mutations in their clotting Factor VIII gene.  This results in them making not-enough Factor VIII, or what they do make is not functional.  Usually if someone has 'hemophilia', they have A (about 85-90%).  Like what they do for the hemophilia B folks, A is treated by IV administration of functional clotting factor several times a week.  To make matters worse, 30% of hemophilia A patients start making antibodies to the artificial Factor VIII.

Know what would be neat?

If we could use a virus to deliver a functional copy of the human Factor VIII gene to these folks genome.

Guess whats in the works?

A virus that can deliver a functional copy of the human Factor VIII gene!

This has just been done in mice, so far, so its way behind what we already saw with Hemophilia B, but these folks are bringing some new and different tricks to the table.

First of all, if you are delivering a gene like this, one of the biggest hurdles is making sure the gene of interest is expressed at a therapeutic level.  While it helps that you dont need a TON of Factor VIII for it to be protective (levels much lower than 'normal' are still protective), all of the gene therapy trials that have failed in humans thus far failed because not enough Factor VIII was produced.  These folks actually found that hybrid pig/human Factor VIII expressed at the best levels!  Well, okay!  And then they tweaked it further so it was harder for the immune system to start making antibodies to the Factor VIII.

They also decided to use a lentiviral system to deliver a functional gene-- Yes, lentivirus.  HIV.  Well, actually they used an SIV background, because it worked better than the HIV version.  Its not real pathogenic SIV-- its just the SIV core proteins that are necessary to deliver the functional pig/human Factor VIII gene.

They also gave the gene a super-charged promoter they stole from cytomegalovirus.

They then pumped the GMO-anti-hemophilia-A-SIV into a mouse model for hemophilia A.  The result?  Four months after the treatment, there was a protective level of Factor VIII in the mice.

Of course, now they need to try it in people.

Really cool first-step, though!

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Could there be a way that this would be expressed in sperm stem cells, or in ova. That is the real "cure."

By Gary Hurd (not verified) on 25 Sep 2012 #permalink

You wouldn't want this expressed in germ cells (sperm / ova). At least not with a lentiviral vector like this. They used the CMV promoter, which is always active. You don't want your sperm, ova, or all their descendant cells (all cells), making Factor VIII.

Now if you could repair the defect, or put in a vector that uses the normal Factor VIII control elements, that would be a better way to go. But at this point in the gene therapy game, it's not considered a good idea to go for germ line correction, as you can screw up ALL cells in the body.

It seems there are several groups trying different ways of adding replacement working copies of genes to ‘fix’ patients with a defective gene, like haemophilia patients. There's also research into treating haemophilia B using (in vivo) genome editing with ‘designer’ zinc finger proteins to create a targeted insertion of a working copy of the gene that came out a bit over a year ago. (I wrote an account of it on my blog.) Just as you’re keen on viruses, I have long-standing interest in zinc finger proteins! :-)

There are also ethical issues with genetically altering the germ line. Doing so imparts permanent genetic changes to someone that doesn't have a choice in the matter which causes some people to cringe at the idea, especially when the other potential side effects are not completely known.

By Poodle Stomper (not verified) on 26 Sep 2012 #permalink