
Haemophilia A trial results 'mind-blowing' - colmvp
http://www.bbc.com/news/health-42337396
======
test6554
This is fascinating! I wonder if something like this could get the pancreas to
begin producing insulin. Type I Diabetes is no joke. It could save tens or
hundreds of millions per year, not to mention multiple injections per person
per day.

~~~
aaavl2821
There are lots of people working on regenerative medicine and gene therapy for
autoimmune diseases (ive worked with several researchers focused on type 1),
but unfortunately the field isnt there yet.

hemophilia a is a disease caused largely by deficiencies in one specific
protein. massive technological breakthroughs in recent years have enabled
scientists to deliver genes to human cells to consistently, accurately and
sustainably produce specific proteins. so treating diseases like hemophilia a
has become tractable

however, autoimmune diseases are much more complex and there is no single
protein or molecule that causes the diseases. in type 1, people have been
trying to discover 1) the "triggering" event and 2) the autoantigens that
cause the disease for years, and it looks like there is no "silver bullet".
current drug technology can target only one, or sometimes two, disease-causing
molecules, so for a disease where many molecules each play a small part, we
dont have the answer yet

there are a few promising type 1 companies (semma, viacyte, others) trying to
turn stem cells into insulin producing cells, but those cells are often
rejected by the bodys immune system. some other companies are increasing the
number of "regulatory T cells", basically T cells that inhibit autoimmunity
(caladrius, celgene / delinia, parvus, lilly / nektar); these have shown
promise but it isnt likely theyd be curative, as they just stop the autoimmune
attack but cant regenerate beta cells that are already lost

if youre interested in type 1 research, diatribe is a great website that
aggregates the latest science and presents it in a way that is easy for non-
scientists, specifically patients and their families, to understand
[https://diatribe.org/](https://diatribe.org/)

~~~
baldfat
Thankfully artificial pancreas are looking like a good option until we can get
to curing type 1. Not only does it save the number of shots like pumps we have
today, but it can measure the sugar level and keep the swings down to a
minimum. [http://www.jdrf.org/research/artificial-
pancreas/](http://www.jdrf.org/research/artificial-pancreas/)

~~~
test6554
They seem good as long as the patient's skin is not allergic to the adhesive
used to attach it to the body. I know someone who had an insulin pump that
worked perfectly except after a day or two, they would get a rash on the skin
and the area would swell up blocking the delivery of insulin.

Nothing like all this great technology that could save your life that is
foiled simply by the type of glue used by the manufacturer.

~~~
baldfat
They go under the skin (Most of the plans I have read)

------
testfoobar
Awesome outcome. But the article is yada-yadaing over the good stuff. How are
the new genes integrated into the patient's body? Why isn't the virus attacked
by the immune system? Instead of regular factor shots, do they need regular
viral-gene shots?

~~~
dekhn
The virus is recognized, but not attacked:

"""After infusion, antibodies to AAV5 were detected in all the tested
participants, but no T-cell–mediated immune responses to AAV5 capsid proteins
were detected, and neutralizing antibodies to factor VIII did not develop in
any participants. The absence of factor VIII inhibitors during more than 1
year of follow-up underscores the safety of AAV5-hFVIII-SQ. As has been
observed in similar clinical trials of vector gene transfer,13,19,29 vector
DNA was detected in various biologic fluids obtained from all the participants
(see the Vector Shedding–Discussion section in the Supplementary Appendix).
The possibility of vector integration was not assessed. The protocol was not
designed to measure whether AAV5 infection was present in family members or
close contacts, and ethics approval was not sought to pursue this question.
The two viral genes within AAV5 have been replaced by factor VIII, and AAV5
requires another virus such as an adenovirus for a productive infection."""

This is a surprising finding because normally AAV5 leads to an immune response
in this kind of treatment, although symptoms are mild and the virus in general
is not considered pathogenic.

The mechanism of integration is described in detail in the wikipedia page.
[https://en.wikipedia.org/wiki/Adeno-
associated_virus](https://en.wikipedia.org/wiki/Adeno-associated_virus)

I think if this worked as intended, no additional treatment is required.

~~~
seren
> I think if this worked as intended, no additional treatment is required.

It is correct if the therapy is targeting all stem cells. I have not
understood clearly from the article but it seems the treatement is targeting
"living cells". Once all your 'fixed' cells have been renewed you would need
another round of treatement.

~~~
Chriky
I have Haemophilia A, I was actually offered a place on an earlier trial
although I didn't do it. It was explained to me that you would not need
further gene treatments even though it targeted adult cells.

I think most cells are made by mitosis and don't come from stem cells.

Here's a screenshot of the explanation I received when I was invited on the
trial -[https://i.imgur.com/H329Vgv.jpg](https://i.imgur.com/H329Vgv.jpg)

> "By using BMN 270 to provide the functional genes, it is expected that you
> may not require treatment for Haemophilia A, as often or at all."

I don't really want to upload the whole Participant Information Sheet because
it contains some of the doctor's personal details.

~~~
jessriedel
Thanks for sharing! Can I ask what considerations went into your decision?
Will you be pursuing this now that there is more evidence that it's effective?

~~~
Chriky
I mean, obviously I regret it now, but at the time I had no idea it would
work. I'm sure the next trial will be extremely oversubscribed! I think my
trial was actually for a low dose version to test safety of the vector and it
didn't have any clinical effects.

Its quite incredible though, there's only a few thousand people in the UK with
haemophilia - this trial just cured like 0.5% of them

~~~
jessriedel
Yea, I definitely was not suggesting it was a mistake with the info you had.
Most clinical trials don't work.

Thanks again for the info. Best of luck!

------
alextheparrot
What a fantastic gateway to show how gene therapy can completely resolve
diseases. Many diseases are as simple as your eyes being brown vs blue - you
simply have or lack particular proteins.

I couldn’t find it on a cursory reading, does anyone know what vector they
used to achieve liver sinusoidal cell specificity? My understanding is that
many gene therapy studies have used blood cells, which can be pulled out of
the body prior to gene therapy, the advances in viral vectors may be just as
empowering as the therapy itself. Imagine, in all the irony, getting
“vaccines” as a child via viral vectors against common causes of poor health
local to your birthplace. An enjoyable quote from a Paul Berg which holds
true, of course - “Fears of creating new kinds of plagues or of altering human
evolution or of irreversibly altering the environment were only some of the
concerns that were rampant”.

~~~
Q6T46nT668w6i3m
_Many diseases are as simple as your eyes being brown vs blue - you simply
have or lack particular proteins._

I wish it were that simple. :(

Eye color, for example, is influenced by a combination of multiple genes.
There’s no straightforward eye color gene. Likewise, it’s especially true for
diseases when something like “stomach cancer” is actually a dozen different
diseases where each is influenced by dozens of different genes that share
symptoms. Combinatorial explosion is a real problem.

~~~
shloosh
Yes, but for any disease there are a number of known gene polymorphisms that
predispose you to the disease. These genes may interact with the rest of your
genome in incredibly complex ways, but I bet all it would take to cure a
disease in most cases would be to target the one or two most prevalent
polymorphisms.

~~~
dekhn
"You bet"? This is one of the core questions in human genomics/health research
today and nobody has been able to make a convincing argument _in general_ that
your proposed approach would work.

~~~
Nomentatus
Would you agree: The question being specifically whether in most cases
necessary-even-if-not-sufficient genetic traits can be found ("genetic
traits", as opposed to "genetic illnesses" since illness may not be the most
likely result.) The problem being that although so far most of our exciting
findings are of at-least-necessary genes (or plural genes, etc); obviously
it's just these sort of cases that will produce high correlations and grab
attention, so there should be a presumption of the equivalent of "publication
bias." Necessarily, these will be the low-hanging fruit even if such cases are
actually the exception, overall.

Of course, mere and relatively small correlations between disease and genetic
traits are extremely common; but there are lots of possible explanations of
such findings. In some cases 16 percent of all genes have a small positive
correlation to a given disease, and "if everybody is at fault nobody is at
fault!"

------
torbjorn
One of the reasons haemophilia appears to be more treatable by gene therapy
(than other diseases) is because the cells that should be producing the
clotting factors are found in the liver. When virus carrying the gene therapy
enters the blood it is collected by the liver's filtration mechanisms,
conveniently aggregating the gene therapy in the tissue that the gene therapy
is targeting.

It is hard to target gene therapy toward specific cells/tissues but the liver
makes targeting haemophilia with gene therapy easier.

------
king07828
This is awesome. I have Crohn's and am looking forward to an eventual cure.

One thing I don't understand is why big pharma and VCs seem to focus on rare
diseases instead of a gene therapy for changing eye color or hair color. With
eye/hair color gene treatments, patients could undergo the therapy multiple
times (if desired) and the pool of patients is all humans (not just rare
diseases sufferers). This allows for amortization of the R&D expense over
substantially more treatments. Plus the advances in gene therapy technology
could then be applied to therapies for rare diseases

~~~
aaavl2821
the cost of manufacturing a gene therapy would probably exceed what most
people are willing to pay for changing eye or hair color. why use gene therapy
when colored contacts or hair dye work, and much more easily reversible in
case you dont like it?

also, it is incredibly expensive to get a gene therapy through fda trials.
there hasnt really been a "true" gene therapy approved in the us yet
(excepting car-t), and the first two approved in europe were pulled from the
market because they werent profitable even at a price of $1M per patient.
thats why these companies go after severe rare disease -- you can charge more
for saving a kids life than you could for changing hair color, and you have to
charge a lot to justify the expense and incredibly high risk of developing a
gene therapy. and with a rare disease, you can go to market with a 20-30
person sales force to cover all patients, whereas to market a hair or eye
color thearpy youd need thousands of people calling on every hair salon and
eye doctor in the country. as of now, the success rate in terms of fda
approval for gene therapy is 0% -- thats an important input in financial
calculations.

further complicating things is that you generally cant dose these drugs more
than once bc your immune system rejects the vector after the first dose, so
you have to get all your economics upfront

~~~
king07828
>the cost of manufacturing ...

>it is incredibly expensive ...

These may be outweighed by the potential market size of 3 billion people (a
rough estimate of everyone connected to the internet). If R&D and
manufacturing have a total cost of 10 billion dollars, then this reduces to
$3.33 per person of the potential market size.

>cant dose these drugs more than once

This may be a showstopper for now. At a certain point, the technology should
improve to allow multiple treatments so that a single individual could have
red hair for a year, blonde hair for a year, black hair for a year, ...

The cool thing about growing blonde hair instead of dying hair blonde, is that
nothing more needs to be done and no further treatments need to be had (unlike
dyes). This does assume that the individual has enough patience for the growth
process

------
sswaner
There is a pretty strong argument that Haemophilia is the disease that has had
the biggest impact on the last 100 years. Russian heir to the throne Alexis
Romanov inherited the disease and his suffering and lack of treatment options
destabilized his family and contributed to leadership issues culminating in
Russian defeat in WW1 and the Russian revolution and the rise of the Soviet
Union.

Agree? If not, what disease led to a greater string of consequences? Malaria,
Spanish Influenza, polio, AIDS?

~~~
openasocket
I'd argue the Bolshevik revolution would still have happened even if Romanov
wasn't a hemophiliac. I don't see how the child's disease would have affected
the management of the Russian supply lines in WWI, or have caused the February
Revolution.

~~~
Nomentatus
It may have been quite helpful in fact; particularly after the invention of
the telegraph, remote amateur micromanagment by royal, tyrannical and elected
HIPPOs (including Hitler and even perhaps even Lincoln at the start of the
war) has crippled many a military effort.

------
pdm55
Another use of a modified virus is to deliver an antibody to VEGF, the factor
that causes macular degeneration (blindness). Prof. Elizabeth Rakoczy has been
recently awarded the 2017 CSL Florey medal for this work.
[http://www.aips.net.au/news-events/the-florey-
medal/2017-pro...](http://www.aips.net.au/news-events/the-florey-
medal/2017-professor-elizabeth-rakoczy/) The video has a cartoon showing the
modified virus being inserted in the retina. I think 40 patients have been
successfully treated in a initial 3 year clinical trial. I found these links
to abstracts of her recent publications,
[https://www.socrates.uwa.edu.au/Staff/StaffProfile.aspx?Pers...](https://www.socrates.uwa.edu.au/Staff/StaffProfile.aspx?Person=PiroskaRakoczy),
but I cannot find an open source research document. Some of her team members:
[http://www.scienceinpublic.com.au/floreymedal/2017-csl-
flore...](http://www.scienceinpublic.com.au/floreymedal/2017-csl-florey-medal-
photos)

~~~
pdm55
Some figures: I got my "every second month" injection of Eylea this morning,
[https://www.macular.org/eylea-injection-
treatment](https://www.macular.org/eylea-injection-treatment). It cost $800
Australian dollars. Under our health scheme, I get $600 back. The guy beside
me in the waiting room has been having injections for 17 & 1/2 years, that is,
since the year 2000. He gets state-assistance to fly down 800 km to our
capital city from the country. The lady across the aisle from me in the packed
waiting room, has a relative drive her down from a regional town every second
week, as she has macular degeneration in both eyes, with the alternate eye
being treated on alternate visits. I give you these cases to illustrate that a
lot of money is being presently spent on treating this disease. I have heard
the incidence of macular degeneration in Australia described as an epidemic.
Obviously, everyone would like a cheaper, longer-lasting treatment. That's
what I am hoping the modified-virus treatment provides.

The figure that jumps out of the page for me in the modified-virus report,
[http://www.aips.net.au/news-events/the-florey-
medal/2017-pro...](http://www.aips.net.au/news-events/the-florey-
medal/2017-professor-elizabeth-rakoczy/), is "This therapy has been licensed
to US company Avalanche Biotechnologies Inc., which has raised over $400
million to progress the treatment through clinical trials and bring it to
market." This figure of US$400 million takes my breath away. I note one of
Prof. Rakoczy's clinical trials in Australia on 32 patients was done with a
AU$370 thousand grant, among others, [https://demo.ands.org.au/long-term-
follow-gene-therapy/10789...](https://demo.ands.org.au/long-term-follow-gene-
therapy/107896?source=undefined). I guess the US$400 million trial will be
more extensive. This means a few more years will have to go by before this
comes to market (if it indeed does).

I have found an open source article about Prof. Rakoczy's trial,
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161436/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161436/).
I note they removed the vitreous humor to place the modified-virus under the
retina (termed a vitrectomy), recording that "It is not yet clear if
subretinal injection can be done safely without vitrectomy". They seem very
pleased with the results of that phase 2 trial.

------
Jemaclus
My wife works on this project! This is so cool to see real-life stories of
this. Awesome.

------
1_800_UNICORN
This could be huge. Hemophilia is one of the most expensive diseases to treat
out there. I worked with a client that provides software to hemophilia
clinics, and while modern factor drugs have made it so that sufferers can live
relatively normal lives, it's still a very challenging disease with many long
term complications.

------
hughes
This is so exciting. I feel like we're really at the cusp of a complete change
in our expectations of how we treat disease, what cures look like, what they
cost, and the range of improvements that can be made to people's lives.

------
tuxguy
The NEJM paper :
[http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article](http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article)

pdf:
[http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708483](http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708483)

------
pishpash
So what was the actual therapy?

That kind of title reminds me of BuzzFeed.

~~~
colmvp
Yeah I apologize, I should've linked to a more informative article.

From another news release:

Investigational SPK-8011, a novel bio-engineered adeno-associated viral (AAV)
vector utilizing the AAV-LK03 capsid, also referred to as Spark200, containing
a codon-optimized human factor VIII gene under the control of a liver-specific
promoter, is being studied as a potential one-time gene therapy for hemophilia
A. It is the second investigational hemophilia gene therapy to emerge from
Spark Therapeutics’ leading gene therapy platform. Spark Therapeutics retains
global commercialization rights to SPK-8011.

We infused a single-stranded adeno-associated viral (AAV) vector consisting of
a bioengineered capsid, liver-specific promoter and factor IX Padua (factor
IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body
weight in 10 men with hemophilia B who had factor IX coagulant activity of 2%
or less of the normal value. Laboratory values, bleeding frequency, and
consumption of factor IX concentrate were prospectively evaluated after vector
infusion and were compared with baseline values.

You read the paper from the New England Journal of Medicine here:
[http://www.nejm.org/doi/full/10.1056/NEJMoa1708538](http://www.nejm.org/doi/full/10.1056/NEJMoa1708538)

------
bluGill
I hope they can expand this to other genetic problems. There are hundreds of
genetic issues science knows about. Just off the top of my head I can think of
high cholesterol, cystic fibrous, and sickle cell anemia. I know there are
others, but I'm just a layman not a medical doctor. Those who have any of the
above would like to be cured.

~~~
andygates
The trick right now is in knowing exactly what gene to express. It's like the
Ionis Huntington's trial, just one well-known gene to suppress (albeit in
cerebrospinal fluid, so the stage 1 trials were interesting). And of course,
the first-wave funding will go to stuff that absolutely, positively will kill
a person stone dead.

As soon as there's multiple targets it gets more complicated. Familial
Hypercholesteroleamia could be any of three genes in it's least complex setup.
I wouldn't be surprised to see a scam "therapy" marketed for it by the end of
the year...

------
mrfusion
Could we do the same thing with sickle cell?

~~~
refurb
Yes, there is a company whose name escapes me working on it - Bluebird? You
insert the correct hemoglobin gene and express it at a high enough level that
you drive the percentage of sickle hemoglobin low enough that you no longer
get the sickle cell crises.

Last I read they were having trouble getting durable expression.

------
toblender
Science, it works bitches.

~~~
dang
Please don't post unsubstantive comments here, and especially not snarky
tropes.

------
toblender
Science bitches.

~~~
toblender
I really wish they had a confirmation screen for comment submitting, or a way
to delete comments :P

~~~
linkmotif
You can delete comments. Can you not? I delete things all the time. But then
again, I just voted yours up :)

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tabs_masterrace
So we can engineer a virus that inserts arbitrary DNA into our cells? What are
the limitations of that? Sounds like the approach could be used for a lot
other useful things.

