8 ms·

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 ha

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”.

carbocation 9y ago
Journal article is at http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article They used AAV (actually, take a look at the article, they give a nice and clear explanation of what modifications they had to make).
will_brown 9y ago
>Many diseases are as simple as your eyes being brown vs blue - you simply have or lack particular proteins. 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.
- carbocation 9y ago
  > the microbiome is what will typically unlock those diseases or not given the gene set 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?
  - ianai 9y ago
    I’ve heard reports that changing out a microbiome has resulted in a few bald people regrowing their hair.
    - TheRealPomax 9y ago
      If you've "heard it", but you can't recall where, you should absolutely not believe your own claims. Either find the source again, or concede that you might have made it up. Because you are the easiest person to yourself to deceive into thinking something that isn't true.
  - toomuchtodo 9y ago
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290017/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290017/ https://www.nature.com/articles/nrg.2017.63 https://www.nature.com/articles/nrg.2017.63 http://blogs.sciencemag.org/pipeline/archives/2017/09/13/wednesday http://blogs.sciencemag.org/pipeline/archives/2017/09/13/wed...
  - will_brown 9y ago
    Well I know without anyone reading or commenting on anything I link to I’ll be downvoted into oblivion for even trying to support conversations I’ve had with multiple physicians, still as a physician yourself I ask you to at least weigh in on the following...is it not true that while genetic mutations can be the sole cause of disease that most disease are triggered by a combination of genetics and environmental factors (i.e. not the same as a protein dictating whether you have brown or blue eyes)? To my point re the microbiome google points to multiple studies including but not limited to: > 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/ 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=subjects_immunology 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/51190/ https://newatlas.com/guardian-gene-gut-bacteria-diabetes/511...
Q6T46nT668w6i3m 9y ago
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 9y ago
  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.
  - aaavl2821 9y ago
    unfortunately that usually isnt the case. there are very few diseases where one mutation or molecule is truly causative. in many areas, weve approached the limits of how much we can treat disease by just targeting one molecule or mutation. this is an area where $50-70B of pharma R&D spend goes each year for the last few decades, and the yield of that research in terms of approved drugs is declining exponentially
  - dekhn 9y ago
    "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 9y ago
      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!"
soperj 9y ago
Doesn't make much sense when my eyes were blue as a kid, but now are green except for a quarter of one eye which is brown.
- todd8 9y ago
  Brown, green, hazel eye colors are variations in the amount on melanin in the iris. This amount can change as one gets older. Babies can have lighter eyes that become darker. 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.htm https://www.sciencedaily.com/releases/2008/01/080130170343.h...
  - Nomentatus 9y ago
    It's likely not harmless but very positive to spread so quickly. I think one hypothesis is the domestication of dogs. They don't usually track fingers, but they do track eyes and having blue eyes may help there. There are many types of melanin - I believe the gene only cuts out one kind.
  - djsumdog 9y ago
    huh. So where does the dominant/recessive traits we learn about in high school play into that? 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.
aaavl2821 9y ago
AAV is the typical vector used for gene therapy. 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
- fgimenez 9y ago
  I sincerely think we are in the gene therapy renaissance. Delivery has always been an issue, but there are new tricks coming out with regard to cell-specific targeting. We can piggy back off the work done for RNA-based therapeutics (mRNA, ASOs, RNAi). 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.
  - aaavl2821 9y ago
    i agree, the hemophilia data looks really good, and avexis' spinal muscular atrophy product looks great as well. i dont know much about voyager but just looked at their press release for the study; looks like they are delivering a gene to increase dopamine production? do you know if this could be a disease altering therapy or just a "better" levodopa? 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
ericb 9y ago
Is the virus transmissible?
- tialaramex 9y ago
  The study did not look at whether family members or other close acquaintances ended up containing measurable numbers of copies of the virus. The patients were tested and the study verified that the (altered) genetic data from the virus was excreted normally. 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.
  - ericb 9y ago
    Thanks for the tldr; I hadn't realized that was possible.
  - djsumdog 9y ago
    Is there any concern that viruses could mutate and once again start to replicate?

carbocation 9y ago

Journal article is at http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article They used AAV (actually, take a look at the article, they give a nice and clear explanation of what modifications they had to make).

will_brown 9y ago

>Many diseases are as simple as your eyes being brown vs blue - you simply have or lack particular proteins. 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.

carbocation 9y ago
> the microbiome is what will typically unlock those diseases or not given the gene set 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?
- ianai 9y ago
  I’ve heard reports that changing out a microbiome has resulted in a few bald people regrowing their hair.
  - TheRealPomax 9y ago
    If you've "heard it", but you can't recall where, you should absolutely not believe your own claims. Either find the source again, or concede that you might have made it up. Because you are the easiest person to yourself to deceive into thinking something that isn't true.
- toomuchtodo 9y ago
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290017/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290017/ https://www.nature.com/articles/nrg.2017.63 https://www.nature.com/articles/nrg.2017.63 http://blogs.sciencemag.org/pipeline/archives/2017/09/13/wednesday http://blogs.sciencemag.org/pipeline/archives/2017/09/13/wed...
- will_brown 9y ago
  Well I know without anyone reading or commenting on anything I link to I’ll be downvoted into oblivion for even trying to support conversations I’ve had with multiple physicians, still as a physician yourself I ask you to at least weigh in on the following...is it not true that while genetic mutations can be the sole cause of disease that most disease are triggered by a combination of genetics and environmental factors (i.e. not the same as a protein dictating whether you have brown or blue eyes)? To my point re the microbiome google points to multiple studies including but not limited to: > 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/ 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=subjects_immunology 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/51190/ https://newatlas.com/guardian-gene-gut-bacteria-diabetes/511...

Q6T46nT668w6i3m 9y ago

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 9y ago
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.
- aaavl2821 9y ago
  unfortunately that usually isnt the case. there are very few diseases where one mutation or molecule is truly causative. in many areas, weve approached the limits of how much we can treat disease by just targeting one molecule or mutation. this is an area where $50-70B of pharma R&D spend goes each year for the last few decades, and the yield of that research in terms of approved drugs is declining exponentially
- dekhn 9y ago
  "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 9y ago
    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!"

soperj 9y ago

Doesn't make much sense when my eyes were blue as a kid, but now are green except for a quarter of one eye which is brown.

todd8 9y ago
Brown, green, hazel eye colors are variations in the amount on melanin in the iris. This amount can change as one gets older. Babies can have lighter eyes that become darker. 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.htm https://www.sciencedaily.com/releases/2008/01/080130170343.h...
- Nomentatus 9y ago
  It's likely not harmless but very positive to spread so quickly. I think one hypothesis is the domestication of dogs. They don't usually track fingers, but they do track eyes and having blue eyes may help there. There are many types of melanin - I believe the gene only cuts out one kind.
- djsumdog 9y ago
  huh. So where does the dominant/recessive traits we learn about in high school play into that? 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.

aaavl2821 9y ago

AAV is the typical vector used for gene therapy. 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

fgimenez 9y ago
I sincerely think we are in the gene therapy renaissance. Delivery has always been an issue, but there are new tricks coming out with regard to cell-specific targeting. We can piggy back off the work done for RNA-based therapeutics (mRNA, ASOs, RNAi). 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.
- aaavl2821 9y ago
  i agree, the hemophilia data looks really good, and avexis' spinal muscular atrophy product looks great as well. i dont know much about voyager but just looked at their press release for the study; looks like they are delivering a gene to increase dopamine production? do you know if this could be a disease altering therapy or just a "better" levodopa? 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

ericb 9y ago

Is the virus transmissible?

tialaramex 9y ago
The study did not look at whether family members or other close acquaintances ended up containing measurable numbers of copies of the virus. The patients were tested and the study verified that the (altered) genetic data from the virus was excreted normally. 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.
- ericb 9y ago
  Thanks for the tldr; I hadn't realized that was possible.
- djsumdog 9y ago
  Is there any concern that viruses could mutate and once again start to replicate?