[HN Gopher] First UK child to receive gene therapy for fatal gen...
___________________________________________________________________
First UK child to receive gene therapy for fatal genetic disorder
is now healthy
Author : ryzvonusef
Score : 188 points
Date : 2023-02-17 19:51 UTC (3 hours ago)
(HTM) web link (www.livescience.com)
(TXT) w3m dump (www.livescience.com)
| dang wrote:
| Related (somewhat):
|
| _First gene therapy for Tay-Sachs disease successfully given to
| two children_ - https://news.ycombinator.com/item?id=30408104 -
| Feb 2022 (77 comments)
| arpanetus wrote:
| you can't just simply state that he's healthy without actually
| seeing his lifespan
| fnordpiglet wrote:
| I for one welcome our new genetically modified UK child overlord.
| mmaunder wrote:
| I wonder if a similar approach can be used for Von Hippel Landau.
|
| " Mutations in the VHL gene cause von Hippel-Lindau syndrome. The
| VHL gene is a tumor suppressor gene, which means it keeps cells
| from growing and dividing too rapidly or in an uncontrolled way.
| Mutations in this gene prevent production of the VHL protein or
| lead to the production of an abnormal version of the protein. An
| altered or missing VHL protein cannot effectively regulate cell
| survival and division. As a result, cells grow and divide
| uncontrollably to form the tumors and cysts that are
| characteristic of von Hippel-Lindau syndrome."
|
| https://medlineplus.gov/genetics/condition/von-hippel-lindau...
| SamBam wrote:
| The article was skimpy on the details. Can someone explain how
| this part works?
|
| > The new gene therapy [...] works by inserting into the body
| working copies of the genes that are faulty in MLD, thus
| restoring the ability to break down sulfatides.
|
| How does the new copy of the gene get into every existing cell
| that needs it? A virus?
| amelius wrote:
| Also, when cells replicate, will the new ones automatically be
| of the edited type? Or is it not that simple?
| janeway wrote:
| That is the goal but not that simple.
|
| In most cases, the original disease-causing stem cells are
| effectively eliminated by the conditioning regimen (high-dose
| chemotherapy and/or radiation) used before the (autologous)
| transplantation, so they do not regenerate and cause further
| harm to the patient. However, in some cases, residual disease
| cells may survive the conditioning regimen and persist after
| transplantation, leading to disease relapse. This is more
| likely to occur in patients with aggressive or refractory
| disease or in those who receive a mismatched or
| haploidentical donor graft. To prevent disease relapse, post-
| transplantation maintenance therapy, such as
| immunosuppressive drugs or targeted therapies, may be used to
| eliminate residual disease cells. Additionally, close
| monitoring of the patient's blood counts and immune system
| function can help identify and manage any signs of disease
| relapse.
| ethanwillis wrote:
| In general it depends. If you modified existing blood cells
| genotype then it wont persist indefinitely. You'd need to
| modify the bone marrow. But then some cell lines work like
| you posed in your question.
| MaryBall wrote:
| Because this therapy edits the stem cells that are found in
| the bone marrow, it essentially means that the disease is
| being fixed at the source. Bone marrow stem cells eventually
| turn into blood cells and immune cells. So if 100% of the
| cells have been edited, then the resulting cells they turn
| into will be the edited type.
| herlitzj wrote:
| https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
|
| This paper seems to have more details on the actual procedure
|
| Patients were treated and monitored according to the schedule
| described in the appendix (p 17) and as previously reported.16,
| 17 HSPCs harvested from bone marrow or mobilised peripheral
| blood (MPB) were transduced with clinical-grade lentiviral
| vector encoding human ARSA cDNA under the control of the human
| phosphoglycerate kinase gene promoter.
| MaryBall wrote:
| Yes, you're right! A lentiviral vector is used to insert the
| working gene into the patient's stem cells. Obviously this is a
| non-pathogenic version of the virus, so it's ability to make
| you ill has been essentially "switched off". However the
| ability for the virus to insert genetic information into the
| DNA of cells remains.
| bglazer wrote:
| Yes, it's a virus, specifically a lentivirus, which inserts its
| own genome into the cells DNA, including the therapeutic gene.
| Looks like they first extract bone marrow from a patient, apply
| the virus which adds the gene, then they put the "fixed" bone
| marrow cells back into the patient (probably after killing most
| existing bone marrow through some really unpleasant
| procedures). The re-inserted, treated cells then expand and
| begin making new cells that have inherited the fixed gene.
|
| In general, gene therapy is probably most useful currently for
| diseases that affect the bone marrow (and the eyes), because
| these are two tissues where you can precisely deliver the
| virus. It's still challenging to control where the virus goes
| and which cells it infects if you just inject it straight into
| the bloodstream.
| meese712 wrote:
| I'm confused how this would reduce disease progression
| compared to a much cheaper allo bone marrow transplant then
| if they are only modifying hematopoietic stem cells since a
| BMT is just doing the exact same thing except with someone
| else's non affected cells. BMTs are a horrific procedure
| though so this definitely has an advantage in that regard.
|
| I would also have to imagine they would have to do
| myeloablative chemo or radiation to make sure the fixed cells
| propagate more than the diseased cell line.
|
| Edit: read the study, they do give them the same chemo used
| for normal transplants.
| piyh wrote:
| Most recipients don't need to take immunosuppressants at
| all if they get PBSC or bone marrow transplants. Even if
| they do, it's short term. Additionally, the allo grafts
| need to be matched, which if you're non white is not a good
| success rate. 85%ish of whites get matched, that number
| gets depressingly low for minorites. On the US registry,
| only 1 in 400 donors get called. I happen to be one of
| those donors and a system where I'm not needed is a better
| one. The best part is no part.
|
| https://ashpublications.org/blood/article/104/12/3501/89040
| /...
|
| >Previous studies have shown that 30% to 70% of all
| patients surviving beyond 100 days after HCT require
| treatment for chronic GHVD,2,4-6 often for more than 2
| years.
|
| Re: a better system is where you don't need donors:
|
| https://www.cbsnews.com/newyork/news/l-i-woman-dies-after-
| ma...
| meese712 wrote:
| I was getting at the article giving the impression this
| somehow cured the disease vs a BMT just slowing
| progression. I know the whole transplant thing sucks.
| I've had two transplants, thank you for being on the list
| :).
| theGnuMe wrote:
| Well it removes graft vs host complications which is a win
| and the requirement to take immunosuppressants for life.
| meese712 wrote:
| Definitely true GVHD sucks. The article gave me the
| impression that they were saying it was somehow superior
| at stopping the disease because it said this "stem cell
| transplants, have sometimes been used to slow the
| disorder's progression in infants,"
|
| (fyi a decent amount of stem cell transplant survivors do
| not have to take immunosuppressants for life)
| [deleted]
| fnord77 wrote:
| > probably after killing most existing bone marrow through
| some really unpleasant procedures
|
| usually a massive dose of radiation, right?
| Traubenfuchs wrote:
| In this specific case CRISPR-CAS9 was used to edit
| "hematopoietic stem and progenitor cells". This means all
| modified stem cells (sadly not 100% of them) will from now on
| produce cells with the gene bugfix applied.
|
| This does not imply that germ line cells were changed and COULD
| mean the person could still have a high risk of making children
| with the original gene defect.
|
| https://pubmed.ncbi.nlm.nih.gov/34882002/
| ryzvonusef wrote:
| > Libmeldy is made using stem cells that are derived from a
| patient's blood or bone marrow and can give rise to different
| types of blood cells, according to the European Medicines
| Agency(opens in new tab) (EMA). These stem cells carry the new,
| functional genes into the body, where they give rise to white
| blood cells that travel through the bloodstream. >
| In clinical trials, Libmeldy offered clear benefits to infantile
| and juvenile patients who hadn't yet developed MLD symptoms;
| these patients were able to break down sulfatides at normal rates
| and showed typical patterns of motor development, for example.
| The benefit of the therapy seemed to last several years, but at
| this point, "it is not yet clear whether it will persist life-
| long, and extended follow-up is needed," the EMA noted.
| > Libmeldy is approved for use in the European Union and U.K.,
| although the U.K.'s drug price watchdog initially rejected the
| therapy due to its hefty list price of PS2.8 million ($3.4
| million at today's exchange rates), BBC News(opens in new tab)
| reported in 2022. The therapy's manufacturer, Orchard
| Therapeutics, then offered Libmeldy to the NHS at a significant
| discount. > The gene therapy has not yet been
| approved by the U.S. Food and Drug Administration(opens in new
| tab).
| jiggawatts wrote:
| https://en.m.wikipedia.org/wiki/Atidarsagene_autotemcel
|
| > The National Centre for Pharmacoeconomics (NCPE) in Ireland
| recommends "that atidarsagene autotemcel not be considered for
| reimbursement unless cost effectiveness can be improved relative
| to existing treatment."
|
| Wow... instead of a lifesaving cure they recommend the treatment
| of the symptoms until the kid dies because it's _cheaper_.
| sho_hn wrote:
| People are often surprised by this, but healthcare and
| insurance systems assign an explicit numerical value to human
| lives and run with it all the time.
|
| https://en.wikipedia.org/wiki/Value_of_life
| xxpor wrote:
| The world doesn't have unlimited resources. You have to make a
| call somewhere.
| elil17 wrote:
| Governments and non-profits already funded the development of
| gene therapy. Letting private companies charge money for it
| and then blocking people who need it from getting it is a
| policy decision.
| whiddershins wrote:
| Doing the procedure has a cost. There must be some pressure
| to reduce the cost, else it will never reduce.
| elil17 wrote:
| I agree there needs to be pressure. Why not regulatory
| pressure?
| sn0wf1re wrote:
| What sort of regulation? Make it cheaper by x% per year
| or we stop using it? Doesn't sound that dissimilar to
| "make it cheaper than the total cost of the current
| treatment or we won't use it".
| elil17 wrote:
| I'd just change the "or we won't use it" to "or your
| patents go away."
| pc86 wrote:
| And then instead of reading "that atidarsagene autotemcel
| not be considered for reimbursement unless cost
| effectiveness can be improved relative to existing
| treatment" today, we would have read something like
| "current regulatory environment precludes research and
| development expenditures into atidarsagene autotemcel" in
| some biopharm prospectus a decade ago.
|
| You can't have it both ways and preventing people from
| making money means, not surprisingly, they will be very
| hesitant to spend money researching those areas.
| krona wrote:
| In quality-adjusted life years (QALYs), there is an upper
| limit to the cost of any intervention because the most you
| can save from one intervention is one life. If the same
| money can be used to substantially improve the lives of 100
| people with other interventions, then the cost-utility
| analysis may say a particular intervention is not
| effective.
|
| You might not like the utilitarian approach but this is how
| the UK measures effectiveness.
| elil17 wrote:
| I do like the utilitarian approach, I just think
| sometimes you need to look outside the box of do A or
| don't do A. If the only options were pay for the
| treatment or don't, then Ireland might be making the
| right call by not paying for it.
|
| Ireland could simply let a local company violate the drug
| patents. A country like the UK could impose conditions
| such as profit caps on pharmaceutical companies who base
| their work on publicly funded research. We could reduce
| the length of drug patents. There are many, many options
| besides "role over and let pharma companies charge $4
| million/treatment when it costs them $1 million."
| ericd wrote:
| From the article: "Libmeldy is approved for use in the
| European Union and U.K., although the U.K.'s drug price
| watchdog initially rejected the therapy due to its hefty
| list price of PS2.8 million ($3.4 million at today's
| exchange rates), BBC News (opens in new tab) reported in
| 2022. The therapy's manufacturer, Orchard Therapeutics,
| then offered Libmeldy to the NHS at a significant
| discount."
|
| So it does seem like they've already discounted it
| heavily.
| ifdefdebug wrote:
| Utilitarian cynism at its best.
|
| The humanitarian approach is to save that one live AND
| improve the other 100 as well. We can afford to do so,
| because those expensive cases are rare.
| lazyasciiart wrote:
| They really aren't that rare, and the reason we don't
| help all of them is not because of a _utilitarian_
| decision not to spend money on public healthcare. If you
| can get your humanitarianism to move that money from corn
| subsidies and fighter jets to health spending, more power
| to you.
| fshbbdssbbgdd wrote:
| If the cost isn't reflective of real resource/labor
| consumption, but instead is a rent on IP (which is
| partially repaying some fixed R&D investment), it's not
| so simple.
|
| Let's suppose a drug company is setting their price to
| maximize revenue.
|
| Suppose they make the following projections:
|
| They determine that if the treatment price is $10 million
| above the actual cost of providing the treatment, 5
| people will buy it. $50 million total profit.
|
| If the price is set so the profit per treatment is $1
| million, 100 people will use it. $100 million total
| profit.
|
| If the profit per treatment is $100k, 800 people will use
| it. $80 million total profit.
|
| If the company isn't factoring in the value of a life
| saved, they will pick the $1 million price point. If
| ethicists then just run with that price, they may come to
| the conclusion that the treatment isn't cost-effective.
| However, they are relying on data that's an output of a
| process with conflicting values, and that pollutes the
| result of their calculation. Garbage in, garbage out. The
| 700 people who didn't get treated lose out for a pretty
| bad reason.
|
| We could imagine a policy where the drug companies are
| mandated to maximize lives saved when setting prices. One
| might argue that companies won't develop as many drugs if
| profits can't be maximized. We could adjust the policy to
| subsidize companies for income lost when setting lower
| prices. Ie. if the drug company picks the $100k price
| point to save 700 more lives, the government gives them
| $20M compensation so they can profit like they would have
| at the $1M price point. That way society spends the same
| amount of money on this drug, but more lives get saved.
| I'm sure there's a lot of challenges in designing a
| program like that, but the opportunity to save lives
| makes it seem worthwhile to attempt.
| theGnuMe wrote:
| There's certainly enough resources for this and any medical
| treatment.
| shadowgovt wrote:
| There are, on the high end of the estimate, 1,600 kids in the
| UK that might have this disease. It's estimated about 5 are
| born per year.
|
| I suspect we can somehow find enough pennies in the couch
| cushions to get those kids a therapy, especially if it's
| curative.
| gambiting wrote:
| The problem is, as always, with allocation of resources. If
| you are running NHS budgets and these treatments cost PS1M
| each(we don't know what price was agreed in the end, but
| let's say it's PS1M per treatment), that's PS1.6 billion to
| treat 1600 kids. PS1.6 billion is a lot of money that can
| save a lot of more than 1600 people if used for other
| therapies. It's a horrible choice to make of course, but
| it's the reality of it. Yes of course the government and
| the country has enough money to afford it - but NHS is
| given a fixed budget.
| linuxftw wrote:
| That would imply that people are dying right now due to
| NHS rationing resources, which NHS will never admit to.
| gambiting wrote:
| Well no, but it could be used to(for example) shorten the
| ambulance waiting time, and that alone would save more
| than 1600 people.
| [deleted]
| kiba wrote:
| That assume the technology never gets cheaper over time.
| I would hope it gets better over time as we cure more and
| more rare diseases.
| vkou wrote:
| > Wow... instead of a lifesaving cure they recommend the
| treatment of the symptoms until the kid dies because it's
| cheaper.
|
| That's the same sort of ethical calculus that goes into
| deciding the distribution of any life-saving resources.
|
| We can always spend more (resources/social capital) to save
| more lives/years of life. How do you decide where that line
| gets drawn?
|
| Most medical systems decide it by looking at the cost of
| treatment (Dollars, organs, risks), and quantifying years of
| quality life gained. If you'd like that bar raised, increase
| the tax rate/insurance costs.
|
| 'Save every life at any cost' is not compatible with a world
| where you have decide whether your budget goes on a low-ROI, or
| a high-ROI intervention. 'First come-first-serve' is not
| compatible with a world where you are optimizing for _overall_
| positive outcomes.
|
| Do you have any alternative guiding principle for where money
| in the healthcare system should be spent?
| Nicksil wrote:
| https://en.wikipedia.org/wiki/Atidarsagene_autotemcel
| cameronh90 wrote:
| What if the cost was $100 trillion?
| shadowgovt wrote:
| Its sticker price is actually $3.8 million. At that price, it
| could be administered to every child in the UK with the
| disease at about the cost of 1 year of the UK's defense
| budget.
| Waterluvian wrote:
| The thing that tires me about this old chestnut is that
| it's just a shell game and not actually a substantive idea.
| "Just take money from somewhere else." It's akin to saying
| that we will use the latest AI technology and machine
| learning to make our value proposition work. It sounds
| satisfying but it says nothing.
| CraigJPerry wrote:
| Why would you need to take money from somewhere else?
| This is misunderstanding how money works for a currency
| issuer.
| Waterluvian wrote:
| Lol exactly. "Just print more money!"
| Gordonjcp wrote:
| It's probably cheaper if you're buying it in that sort of
| quantity. Three million quid on this, three million quid on
| that, three million quid over there, soon you're talking
| about a lot of money.
|
| If you buy 1600 doses of it at a time they're going to
| sharpen the pencil for you.
| mrtksn wrote:
| What happens if UK requires defense that year?
| hummus_bae wrote:
| Another country where nationalized healthcare is a bad idea.
| shadowgovt wrote:
| Not sure I follow. It's not like a therapy with a sticker
| price of $3.8 million is more available in countries without
| nationalized healthcare.
| mrtksn wrote:
| In Europe they have these things called planes, it's like a
| tube you enter and sit for a few hours and once exit you are
| in a driving distance to American hospitals where you can pay
| and receive the same treatment as everyone else without
| nationalised healthcare.
|
| Best of the both worlds.
| gambiting wrote:
| What's more, Europe also has these private hospitals which
| aren't connected to the national healthcare system and
| which will provide you with top level care if you are
| willing to pay, no travel to US necessary. Private health
| insurance ( _gasp!_ ) is also a thing, should you want to
| partake in that system.
| blibble wrote:
| I think you'll find most insurance policies have a maximum
| nivenkos wrote:
| But healthcare isn't nationalised in Ireland. Was that your
| point?
| ls612 wrote:
| [flagged]
| OscarTheGrinch wrote:
| I think a full time caregiver of someone incapacitated should
| have the power to vote on their behalf. This is a big chunk
| of society, yet seemingly invisible to politicians. Perhaps,
| if people with disabilities and illnesses couldn't be just
| ignored as "non voters" they would be more of a priority.
| gambiting wrote:
| But....they can? You can give someone else the power to
| vote on your behalf if you cannot do it yourself. Unless
| you mean that if someone is literally unable to make any
| decisions by themselves their caretaker should be able to
| vote on their behalf how they think this person would vote?
| That doesn't strike me as a very reasonable system, you
| can't know how someone would vote unless they tell you, and
| to assume you can or should know is irresponsible.
| gambiting wrote:
| That's such a reductive, dismissive take on the issue it's
| actually offensive towards everyone in this country trying to
| make the healthcare system work. The government isn't ran by
| some cartoon villains, and the resources at NHS's disposal
| are finite - I certainly don't envy anyone whose job it is to
| make sure they are allocated in the most efficient way that
| also saves the most lives.
| A4ET8a8uTh0 wrote:
| << The government isn't ran by some cartoon villains
|
| I will make a short quip here. All cartoon villains I saw
| appear to be fairly capable administrators. If government
| was ran by one of those, we would likely see an
| improvement. I am not sure who is in charge anymore, but I
| can agree with you that it is not cartoon villains.
| wellanyway wrote:
| But caaapiiitaliiism
| robocat wrote:
| > because it's cheaper.
|
| Compromises _always_ have to be made because the world does not
| have infinite resources. Unfortunate, but true.
|
| One way to allocate resources between all our competing needs
| is by using money.
|
| You can come up with other systems of allocation, however all
| systems will be unfair and arbitrary in surprising ways. There
| is always a need to choose between ugly choice A and ugly
| choice B, because our resources are constrained.
| timerol wrote:
| Here's the study: https://www.ncpe.ie/wp-
| content/uploads/2021/04/Libmeldy-Bene...
|
| It's worth mentioning that the study in Ireland indicates that
| the treatment extends life by 14.49 QALYs (average "Total Life-
| years" moved from 8.92 to 22.74), which is a long way from a
| cure. If this is truly a cure, and the treated population lives
| a full life (life expectancy in Ireland is current 82 years,
| not 23), then this treatment will become cost effective without
| any change in the treatment or it's cost. The posted article
| agrees that this is the big open question.
|
| > The benefit of the therapy seemed to last several years, but
| at this point, "it is not yet clear whether it will persist
| life-long, and extended follow-up is needed," the EMA noted.
| jiggawatts wrote:
| They _can 't possibly_ know that the drug extends life to
| "22.74" years, because it has only been approved for use for
| the last 3 years! This is like asking for 30 years of
| Kubernetes experience on a job application.
|
| Even if the estimate is accurate, there is a massive
| _qualitative_ difference between slowly dying horribly for
| 'x' years and living a normal life for 'y' years. You can't
| just subtract 'x' from 'y' and come up with a delta and
| compute based on that.
|
| Reminds me of the studies that showed that Tamiflu is
| ineffective because it only reduced the _duration_ of
| influenza symptoms by 1 /2 a day on average. Yes, that's
| true, I've taken it myself and the symptoms continued for
| about the normal period of time. But it reduces the
| _severity_ massively. It 's like a light switch. The most
| severe flu suddenly turns into the mildest of mild cold-like
| symptoms in a matter of hours. But... that's hard to measure
| objectively, so it is not recommended because the according
| to a metric that doesn't matter it doesn't work.
|
| The statistics and metrics in medical papers are _woeful_ ,
| which is why it's commonly accepted that 1/2 of all medical
| research is false.
| [deleted]
| themaninthedark wrote:
| And this in turn leads people to be against national health
| care as they are worried that the government will be the one
| making the decision that it is cheaper to let people die rather
| then treat them.
| Gordonjcp wrote:
| As opposed to insurance companies making the decision that it
| is cheaper to let people die than potentially adversely
| affect shareholder value by treating them?
| ryeights wrote:
| Such power is already vested in undemocratically governed
| private insurance companies, no? I can't imagine any health
| insurance plan would have covered this treatment.
| TSiege wrote:
| Except that reality is you vote for government, not for the
| health insurance industry
| CommanderData wrote:
| Don't some insurers outright deny cover for chronic or
| genetic conditions?
| vondur wrote:
| People tend to react differently when the learn it's a
| government bureaucrat making decisions on healthcare.
| However, people will also howl when they find out it the
| decision from a cruel penny pinching CEO. These are really
| difficult problems. How much is too much to save a life?
| csours wrote:
| Yes, someone somewhere will be making this decision. It
| could be insurance, a doctor, nurse, hospital
| administrator, or family member, or even the affected
| individual.
| nradov wrote:
| In the US, medical insurers are not allowed to deny
| coverage for chronic or genetic conditions due to the
| Genetic information Nondiscrimination Act of 2008 (GINA)
| and the Affordable Care Act of 2010 (Obamacare). Some
| treatments may require proof of medical necessity, or
| require that providers and patients try lower cost options
| first (step therapy).
|
| Rules for life insurers are different and in some
| circumstances they may deny coverage.
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