A long time ago, in a galaxy far far away, ‘visionary’ scientists like Francis Collins thought ‘genetic diseases’ were coming to an end. Because they believed in ‘OGOD’, ‘one gene, one disease’ (lol, *blink*), they were sure identifying ‘disease’ genes would… somehow… give us the ability to cure said diseases.

Unfortunately, even ignoring the technical issues weve had with gene therapy, OGOD isnt exactly how genetic diseases work. Yes, some are caused by one dysfunctional gene, like X-linked ALD I wrote about earlier, but many more are caused by a constellation of genes, environmental stressors on those genes, infectious agents colliding with malfunctioning genes at just the right time…

I dont want you all to get the impression that treating/curing genetic diseases is going to be as ‘easy’ as the previous post made it out to be.

This is the case with a form of blindness– Lebers congenital amaurosis (LCA). People born with this disease progressively go blind in infancy-childhood. There are numerous forms of LCA caused by a combination of 13 genes. Where do you start when youre trying to treat a multifactorial disease? Take small steps. Simplify it.

Researchers knew 6% of all LCA cases are caused by a defective RPE65 gene. Without this enzyme, you cant metabolize Vitamin A (EAT YOUR CARROTS!), you go blind.

So they started there:

Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial.


This gene therapy trial is absolutely nothing like the one I described earlier.

The first one was more elegant– grabbing the positive attributes of three viruses, putting them together for your end goal.

This study is less ‘elegant’ and more ‘brute force’.

They packaged a functional copy of RPE65 into an adeno-associated virus. AAV is a weird little bugger– its not a retrovirus, but it has the capability of inserting its double-stranded DNA genome into our genome. Unlike retroviruses, which insert randomly, AAV actually has this one spot it can insert, in chromosome 19! One spot! And its by accident, virus dont wanna be there. BUT, this virological quirk is something we can capitalize on for gene therapy!

While this insertional quirk has its advantages (the DNA is not going to insert into a tumor suppressor, or activate an oncogene), it also has its disadvantages. The virus dont wanna do it. Insertion is an accident. So to get this virus to work for gene therapy, you have to use A LOT OF VIRUS to increase the odds that this improbably event.

Brute force.

So researchers injected 1.5×1010 to 1.5×1011 viruses directly into one eye of 12 LCA patients 1-2 years ago.

All can now see better in dim light, have an increased visual field, their pupils respond to bright light.

Seven of the 12 have increased visual acuity.

And all of the kids involved… None of them could navigate a small obstacle course scientists set up for them pre-treatment. One video is this cute little boy, nervously twisting his shirt, and just standing there. He was afraid to take one step on the course. He couldnt see anything.

Yeah, after treatment, all the kids could navigate it. That scared kid? Brazenly flies through the course in a minute. No hesitation. And acting like a dopey 10 year old boy.

I teared up watching the transformation, I dunno how the researchers werent bawling.

Its gonna be awesome when gene therapy develops from scientists nervously twisting their lab coats, taking small steps, to us blazing through more complex gene networks without batting an eyelash.

Comments

  1. #1 Dawn
    November 13, 2009

    Erv…can’t see the videos at work, but just your description has me tearing up! Thanks!

  2. #2 Bryan
    November 13, 2009

    OGOD is more or less what you get when you think that the genome is “perfect”, and has been corrupted. Why would complex multigenetic relationships emerge on a substrate of perfect operation?

  3. #3 JustaTech
    November 13, 2009

    I think I worked on this when I was manufacturing therapy-viruses. Was this first studied in dogs, a specific breed of poodle-y things?It sounds really familiar, and I’m so excited that it works! That’s totally awesome!

  4. #4 BeamStalk
    November 13, 2009

    That is just some awesome stuff.

  5. #5 Sili
    November 13, 2009

    I dunno how the researchers werent bawling.

    Because they’re cruel, ebol, heartless Nazis, who enjoy sticking needles in the eyes of poor, defenceless kids. NEEDLES WITH VIRUSES! AIDS IS A VIRUS! HOW DO YOU LIKE DEM APPLES!!

  6. #6 ben
    November 13, 2009

    Justatech- Lebers congenital amaurosis has a naturally occurring knockout model, the Briard dog. I work on a mouse model that we originally though might have reduced expression of RPE65 and remember when the preliminary results of gene therapy of this disease were being published in animal models. Although my own research has led away from this area (so I’m not frantically checking pubmed for RPE65 every 12.5 seconds to see if anyone is scooping me) it’s nice to see the escalation to human trials and get a virology perspective.

  7. #7 The Backpacker
    November 14, 2009

    I love gene therapy using viruses to help people seems like raiding the enemies’ weapons cache using their own guns against them. It is almost subversive in a way.

  8. #8 Daniel J. Andrews
    November 16, 2009

    No need to put “visionary” in quotes. One might think you’re being disparaging of people who dared think big. If Collins and others had been right, they would have been visionaries. A visionary is just a dreamer who happened to have one of his many predictions or musings come true.

    Most visionaries have many more misses than hits because their nature is to go dream about how far we may go beyond current knowledge. It isn’t how wrong they are that people remember, but how right they are when they actually are shown to be right.

    And be careful how you judge those in the past with the knowledge of today. Some things may indeed be lol, *blink*, but often only by current knowledge, and not by the knowledge available at the time. A long time from now maybe some historian might stumble across some of your posts and do the lol *blink* at some posts here.

    There’s more than just knowledge too…it takes a while to break away from past prejudices, thoughts and cultural influences. Avery et al’s work (circa 1940-45) pointed fairly strongly to DNA being involved in inheritance, but that work was largely not accepted as proteins were thought to be involved, and proteins were being touted by influential scientists (e.g. Linus Pauling). [hoping I correctly remember my basic biology history here]

    Anyway, not to take away from a fantastic exciting discovery…thanks for posting it.

  9. #9 Aingon Atelia
    December 17, 2010

    Amazing story. I just heard you on Dr. Kiki (I’m a little behind in my listening) and found you interesting and informative. I was telling a friend about this, and hunted down the ep on Kiki’s site.

    Then I went to her site and watched the video. Smart *and* pretty. Great combo. Too bad I’m not younger. ;)

    AA

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