Haemophilia A trial results 'mind-blowing'
bbc.com
bbc.com
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/
I often hear it said that problems such as this are caused by cures being less profitable compared to drugs, because drugs are purchased repeatedly, cures only once. But competition is supposed to solve that problem. Is inappropriate regulation the real problem?
Nothing like all this great technology that could save your life that is foiled simply by the type of glue used by the manufacturer.
If not, gene therapy can only be applied pre-emptively, I guess, unless we somehow manage to isolate the mechanism of how measles resets the immune system, and apply it selectively to the part that has learned the autoimmune behaviour[0].
[0] http://www.sciencetimes.com/articles/6168/20150508/measles-w...
the genes involved in autoimmune disease are not as well understood as in some other diseases, and the individual contribution of any one gene is pretty small in autoimmune disease (compared to, say, spinal muscular atrophy). so as you say, a gene therapy approach might not be the right tool for the job.
a lot of current approaches focus on "retraining" immune cells to be "good" rather than "bad" cells. here's a blog post about one of the leading startups in the space which was acquired by celgene, a large biotech company, for almost $800M earlier this year, just 3 months after raising their series a: https://lifescivc.com/2016/09/re-balancing-immunity-via-regu...
And despite all of the amazing technological and medical advances over the past 10-20 years, the best insulin therapy in the world is still comically shitty when compared to a healthy pancreas.
Anyway, it could be way worse and I'm grateful for what is available to us today. Still hope for better days ahead.
"Modified blood stem cells reverse type 1 diabetes in mice"
https://www.diabetes.co.uk/news/2017/nov/modified-blood-stem...
And type 2 got cured by an extreme diet in 86% of patients:
https://sciencealert.com/extreme-diet-reverse-type-2-diabete...
the most common animal model for type 1, the NOD mouse model, is notoriously bad. studies have shown that loud music cures diabetes in these mice. mice raised in one lab get diabetes differently than mice raised in another. the immune systems of these animals are very fickle and almost any environmental perturberance can change an immune response
I realize the mind recoils instinctively at these ideas, but it seems so frustrating and horrific that we have to delay life saving medical advanced due to insufficient experimental subjects.
safety studies are not the largest driver of cost and duration of drug development. failing a later stage human study that assess effectiveness is a much bigger needle mover in terms of cost, as is the arduous and painstaking process of early drug discovery and development. human studies of effectiveness cost $15-500M+ and can take 3-7 years. putting a drug in humans that has a low probability of success is the most value destructive thing you can do in pharma. the other big cost driver is early research in drug discovery and development. understanding the biology and chemisty, developing assays, and screening compounds can cost $15-20M+ and take 5+ years. by comparison, animal safety studies cost maybe $5M and take a year or two
For more context:
There's an important distinction to be drawn between two main types of animal models: models assessing drug "safety", and those assessing "effectiveness". the models of effectiveness are very poor and of questionable value in some cases, although they are often the best we have. animal models of effectiveness are not literally required for FDA approval, although in reality they pretty much are
animal models of safety, however, are required by FDA, and rightly so. they are of much greater value. generally you must do studies in a small species like a mouse as well as a non-human primate. these "toxicology" studies basically entail dosing animals with huge amounts of drug, way more than you'd dose in humans, and then seeing what doses are not toxic. this informs the first dose youd do in humans
the initial human studies are not done to study effectiveness, but to study safety. based on the data from your tox studies in animals, as well as other studies, you gradually dose cohorts of patients with higher doses, watching carefully for safety signals.
This trial was phase I/IIa which I believe means it's combining safety in humans with initial efficacy data. The thinking is, the real treatment is a single dose. If we give participants less than a full size dose we don't learn much from that. If we give them a real dose, we might as well see if it works.
So their endpoints were firstly how is the treatment tolerated, then secondly does it reduce the need to take clotting factors? Hence this good news story.
"""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
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.
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
> "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.
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
Thanks again for the info. Best of luck!
The increase in the pipeline of gene therapies just in the past few months has been incredible.
Here are the ones I'm tracking: BioMarin valoctocogene roxaparvovec (BMN-270) Spark SPK-8011 Sangamo (Pfizer) SB-525 Bioverativ BIVV-001 Shire SHP-654 (BAX-888)
> As for the liver, the human body's detoxifier, its cells' lives are quite short - an adult human liver cell has a turnover time of 300 to 500 days.
https://www.timeshighereducation.com/news/life-span-of-human...
So I think it must be targeting the stem cells or this wouldn't last more than a year or two? EDIT: See Chriky's comment.
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”.
They used AAV (actually, take a look at the article, they give a nice and clear explanation of what modifications they had to make).
I think the other half of this is the microbiome. I have been speaking to physicians about leaky gut recently and a great analogy is the protein genes are like a piano and the microbiome is like the musician.
As you suggest the genes/piano is sort of the hand you are dealt (you have the gene for certain disease or not), but the microbiome is what will typically unlock those diseases or not given the gene set. Another way of explaining this is that humans have about 20,000 genes, the most genes in any animal are about 35,000, and wheat has 164,000-334,000 genes. Obviously we are much more complex with the potential to carry many more diseases which physicians explained to m through humans having a microbiome.
If true, that would be a Nobel-worthy finding. I don't think this is true, but do you have a citation supporting this for the "typical" genetic disease?
> Here are just some of the health conditions that involve our microbes: Acne Antibiotic-associated diarrhea Asthma/allergies Autism Autoimmune diseases Cancer Dental cavities Depression and anxiety Diabetes Eczema Gastric ulcers Hardening of the arteries Inflammatory bowel diseases Malnutrition Obesity
http://learn.genetics.utah.edu/content/microbiome/disease/
>Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome.
https://www.nature.com/articles/nrg.2017.63?WT.feed_name=sub...
>Researchers have discovered that a powerful guardian gene known to protect against a variety of autoimmune diseases, including type 1 diabetes, is triggered by the bacteria in our gut.
https://newatlas.com/guardian-gene-gut-bacteria-diabetes/511...
- You need a combination of genetics + environment to have a phenotype (whether disease or otherwise)
- Several conditions have a relationship with the gut microbiome
Also, I think you will enjoy this absolutely amazing study that found that the gut microbiome drives cerebral cavernous malformations(!!!) by interactions with TLR4: https://www.nature.com/articles/nature22075
So, I just don't think that "typically" the gut microbiome is the driver of disease. In fact, it's a rare enough find that people get Nature papers out of it. But, if it is actually typical, then I stand by my assertion that someone will eventually get a Nobel prize from proving it.
people are studying microbiome therapies for cancer, autoimmune disease, cns disease, etc, but its way too early to tell if any of it is real. there are many challenges: how do you ensure the microbes you administer stay in the body, colonize, and actually produce the molecules you want them to? how do you manage the risk that they interact with other microbe populations in ways that are impossible to predict accurately, but potentially very harmful? how do you manufacture these things in a consistent, high quality way? what is the regulatory path? how do you justify a huge risky r&d investment when you can't patent a microbe? not to mention the biology risk; the "microbiome thesis" sounds nice, but how confident are we that microbes can treat cancer, depression, parkinsons? right now, not very
I have a genetic disorder. Working on my gut health has gone a long way towards reversing my symptoms.
I don't talk about it as much as I used to because it was a constant shit show from people being completely dismissive, outright calling me crazy and asserting utterly illogical things in the name of their "scientific" bias, like "Your 13+ years of steady forward health progress in the face of your degenerative condition is merely wild coincidence and doesn't prove that you know anything at all. Stranger things have happened!"
Cuz, yeah.
People who see themselves as scientific and logical are very often not remotely objective. They just have college degrees or whatever to justify their ugly personal prejudices, and don't confuse them with the facts.
One could just as well argue that because the immune system is so well developed and robust in the gut that it's the last place to look for dysfunction. Or one could argue that a 70% share of immune cells is rather low considering the relative ratio of environmentally-exposed surface area.
We could say all kinds of things if we're free to make unsubstantiated conjectures. But we really can't say anything of substance without context and evidence. The human organism is ridiculously complex and consistently defies intuition.
I don't agree, but I appreciate the expanded perspective.
The way I used to describe it was that your genes are like the blueprints for a house and what you eat is like local building materials. The blueprints may specify 2 bedrooms, one bathroom, but exactly how that will look will depend a lot on the vernacular architecture. Is it adobe brick because you live in the American Southwest? Is it made of blocks of ice because you are an Inuit? Etc.
So, different building materials have different strengths and weaknesses. This will significantly impact things like ceiling height and room size because what shapes the material supports will vary, depending on the material.
I'm sorry some people are reflexively downvoting. I hate it that so many people who imagine themselves to be scientific are so incredibly dismissive of stuff like this.
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.
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!"
(+ obvoiusly the stuff from the other comments about how hard it is to determine the cause to begin with)
As a personal example, a close family member was recently diagnosed with shwachman-diamond syndrome (SDS). I have confirmed with multiple leading physicians (Dana Farber, Mayo Clinic, etc) that all of the tools necessary to cure her are presently available. At a high level, this would involve: 1. Extracting marrow. 2. Isolating blood-cell producing stem cells & amplifying in a dish. 3. Modifying using a product like [A] 4. Validating/re-sequencing to confirm transduction. 5. Re-insert modified cells into patient.
Yet doctors can't engage in this work without going through the lengthy drug trial process. So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
[A] - https://crispr.sigmainformatics.com/templates/CRISPR%20Custo...
On the other hand, something which is exceptionally well known to work should also attract huge and immediate capital to do the proper tests. Even for rare diseases, a sure thing would be funded.
I think the difficulty is more about procedural or cell based cures vs. drug-based cures or treatments. The system is set up for the latter, but is not comfortable with the former.
Only if there is a ROI. Which also means that even treatments for not-so-rare diseases don't get funded if the majority of patients won't be able to afford the treatment at a price that provides that ROI. Clinical trials in the US or Europe are insanely expensive and you cannot even budget them: Adverse reactions by "male patients over 45, born on a new moon Tuesday"? In worst case you restart the trial, excluding the problematic group to at least get the proof of safety and effectiveness for some part of the population so you can finally make some money...
On the more consumer side of things, being able to fix some sort of obnoxious but perfectly survivable condition that genetic engineering may be able to solve (say lactose intolerant) may be something that you could sell to a lot of people.
For Medicare or certain people on Medicaid it might be worth it.
This is a bit of a leap. In principle (some of) the technology "is there" but there is a huge amount of complexity in the steps 1 through 5!
> Yet doctors can't engage in this work without going through the lengthy drug trial process.
I think it needs to be said that the "lengthy drug trial process" exists for extremely good reasons. Were a treatment to be shown to be so incredibly effective during the trial process, based on pre-defined statistics monitored by an independent data safety monitoring committee, the trial would be stopped as it would be unethical not to provide all patients with the clear benefits. (recent example: https://www.ncbi.nlm.nih.gov/pubmed/29132880)
> So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
I believe it is unquestionable that doctors should be advocating treatment based on the best available evidence, and that the process for obtaining said evidence is a thorough and rigorous as possible, otherwise great harm can be done (classic example, thalidomide).
I would question the doctor that routinely recommended an experimental treatment which has not been shown to be efficacious over a "risky procedure" which has been shown to have $X efficacy.
Making patients aware of trials which may be of benefit to them is a valid and valuable part of medical practice, which is not always done very well. This is improving (in the UK at least) with greater numbers of research nurses and the use of databases such as https://www.ukctg.nihr.ac.uk.
Excuse my ignorance here, but has there been a single other drug that the FDA has stopped before it became an issue that a less insanely thorough process wouldn't have? It seems like the FDA was right about thalidomide and has been using that as justification ever since. At this point, clinical trials have become so onerous that the FDA can't even vet them and just trusts the drug companies to be above board.
Blue eyes are believed to be caused by an isolated, inherited gene, OCA2. This gene is present in all people that have blue eyes. It disables the production of melanin in the iris.
All blue eyed people are believed to have a common ancestor from 6000 to 10,000 years ago, the first person with blue eyes (originally caused by a random mutation). It’s harmless enough that lots of us have it now.
See [1].
[1] https://www.sciencedaily.com/releases/2008/01/080130170343.h...
I ask because my niece had blue eyes as a baby. This didn't make any sense because my sister was Indian, our parents were from India, their parents were from .. well I guess now it's Pakistan, but they migrated during the partition.
My sister married a white dude, but still it seemed very unlikely her daughter wouldn't have brown eyes. That's when we found out my grandmother got her education in Europe, and came back pregnant. Apparently divorces at the time were so shameful that it was better to tell your child their parent died.
My nieces eyes are now a bit hazel/blue-green ish. My grandmother passed away not too long after that, and that secret would have died with her, if it wasn't for the fact that my niece had blue eyes.
viruses are useful because they have evolved to insert foreign DNA into host cells. nothing humans can conceivably engineer has come close yet to the ability of viruses to do this
however viruses have also evolved a lot of bad qualities that cause disease. AAV is nice because 1) it is not known to cause disease, 2) only causes a mild immune response (so the body doesnt reject it before it does its work) and 3) is replication defective, so it wont reproduce uncontrollably in your body
all that said, viral vectors are far from perfect. the biggest issue is that you can usually only inject them once. after one injection, the immune system learns to recognize the virus as foreign, and upon subsequent administrations it will kill the virus before it can transfect cells. also, there is some risk that the viral genome can integrate with the host genome in ways that arent ideal.
from what i understand, the liver and the eye are really the only easily targeted specific tissues. the viruses are naturally carried to the liver, and the physiology of the eye enables viruses to get into cells there easily. getting viruses just to the brain, or heart, or pancreas, is much more challenging
aav technology has been around for a while, but there have been many false starts. back in the late 90s there were copmanies delivering genes into the brain with AAVs to treat parkinsons and alzheimers, and the genes got integrated and expressed by the right cells. however, the diseases were too complex for just one gene to cure them. in many ways, the advances in biology are enabling us to find what diseases are "right" for gene therapy, althoguh vector tech has improved as well
As for the CNS - Voyager therapeutics has had some great readouts in September in gene therapy for Parkinson's. More data coming out in Q1 to see second part of study.
its still pretty hard from what i can tell to deliver oligos to specific cells. delivery has been a huge challenge for ASOs, mRNA etc. viral vectors and autologous cell therapies have been used but have limitations, and antibody-tagged "targeted" nanoparticles have also been tried with varying degrees of success.
theres been some really clever developments in delivering oligos with cationic lipid nanoparticles to macrophages. biontech has an approach where theyve made nanoparticles that are naturally taken up by macropinocytosis by dendritic cells and macrophages. if you get the overall charge of the nanoparticle right (net negative i believe), the dendritic cells migrate to the spleen (rather than the lung with positive charge), where they can present antigen encoded with mRNA to t cells. they also have some interesting mRNA tech that increases the transfection efficiency, as it is hard to prevent oligos from getting degraded in lysosomes before they are translated. genentech paid them $310M upfront for a preclinical asset
Also correct about general delivery difficulties. Hadn't heard of Biontech's method - almost sounds like voodoo by your description.
I think there is interesting blocking and tackling happening on an organ-by-organ basis. E.g. GalNAc for liver hepatocytes, LNPs for systemic mRNA therapies, direct injection for eye or CNS (cheating, but still works). I'm partial to exosome hype...
Also no such discussion is complete without saying CRISPR, but the point remains that you can conjugate it targetted vehicles like antibodies. Conjugating to antibodies seemed to work for Stem :p
out of curiousity, what's the exosome hype? ive heard a few strong life sci VCs mention it, but i talked to a ceo of an exosome company and didnt quite understand the specific therapeutic potential
Happy to geek out more offline. Email in my profile.
id imagine the immunosuppressive dose would have to be pretty strong and come with a host of other risks. i know the immunosuppression load for gvhd is pretty heavy, and corticosteroids are not fun drugs
The virus was deliberately defective and unable to replicate, so the copies made for use in treatment are the only copies that would ever exist. This also ensures that dose control is effective, if the virus could replicate then further copies of the gene would be inserted.
It is hard to target gene therapy toward specific cells/tissues but the liver makes targeting haemophilia with gene therapy easier.
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
Second, I can see some potential for major backlash. Literally going into the business of designer babies? Ethically tricky. Doing it only for the rich, because it'll be incredibly expensive at first? "Tricky" doesn't begin to cover it. Public policy in first-world countries is not always noted for being far-sighted and even-handed, and a public backlash could easily shut down all gene therapies.
Agreed. The joke being that black hair (or blonde hair or red hair) is a disease that can be "cured" by a different hair color :)
>backlash ... [against] designer babies
Agreed that this is an issue, especially if the treatment were marketed at unborn children. It may be better to focus on cosmetic treatments for adults to try and avoid this.
I expect this technology will eventually become ubiquitous in our lifetimes, with the only question being the time frame for which it will come to pass
The less expensive means (contacts, hair dyes) are temporary and require maintenance. The benefits of a genetic treatment is that it is permanent (no cleaning of contacts, no subsequent salon visits), but should also be reversible
Check this out, it has a lot of interesting information: http://www.crohnsmapvaccine.com
Could be interesting although obviously still in phase 1.
from the link:
>Historically, MAP in humans has been difficult to study as it cannot be seen under an ordinary microscope and is very difficult to grow. Testing for MAP by the presence of its DNA (using PCR) has found MAP in up to 92% of Crohn’s patients but until now no-one has developed a test to show MAP in-situ in the tissues of people with Crohn’s disease.
It is fascinating that there is a virus that evades regular diagnostic techniques (i.e., using a microscope). That the virus can be found using genetic testing speaks to the power of genetic technology and how revolutionary the true understanding of genetics will be
Regarding the substance of your remarks, if 10,000 people have a rare disease then the 100 million dollars it takes to develop that therapy can only be amortized over that small pool, which translates to $10,000 per person, assuming that every person pays for the therapy.
If 3 billion people (a rough estimate of everyone connected to the internet) is the market size for hair/eye color treatment and the 10 billion dollars of R&D gets amortized over that full-size, then the cost is $3.33 per person. If only 10% of people want to change colors, and only 10% of those people are willing to partake in the therapy, then the cost becomes $333.33 per person to amortize the R&D expense, which is in the same order of magnitude as contacts or a salon hair treatment.
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
>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
Agree? If not, what disease led to a greater string of consequences? Malaria, Spanish Influenza, polio, AIDS?
We'd likely live in a very different world had it been prevented or curtailed, though it's hard to know what specifically would be different, as even the existence or non-existence of a single person could be pivotal in history.
The follow-on Kerensky government proved even less effective militarily, although it can be argued that the consequences of a century of mismanagement favoring the 1% wasn't easily reversed.
Malaria has defeated many an army and invasion; yellow fever, too. The fall of Rome has been blamed on a severe plague; particularly the fact that Rome was hit last, and therefore weak when it's neighbors were recovering and stronger.
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..., 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.... 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/. 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.
That kind of title reminds me of BuzzFeed.
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
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...
Last I read they were having trouble getting durable expression.