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Well this is incredible. Can someone give me a mid-level explanation of how the medicine gets into the right cells (and the ramifications of the medicine going into cells that do not need it)? Is it simply shoot the medicine, hope the right cells are affected, and if not (later, assuming it is found safe) just inject more until all cells that need corrected have received the gene edit?
You can create constructs that will only be expressed when ~~someone~~ something* else is present in the cell.
If you’re injecting into an eye cell, you could make your construct such that it only is turned on when is present. Since eye cell will always express that protein, but testicle will not, you can now see from your eyes instead of your balls.
In CRISPR, it isn’t actually a protein that you target, but a specific DNA sequence that’s targeted with guide RNA.
This guide RNA tells CAS9 protein “hey come here”.
And then old sequence is snipped out and new sequence is inserted.
But dna/protein are closely related so hopefully you get the right kind of idea.
I also might be wrong but this is my understanding
Excellent, that makes sense. Thank you! I didn't know about the ability for it only to activate if something else is present.
> Since eye cell will always express that protein, but testicle will not, you can now see from your eyes instead of your balls.
Aww, nuts.
I wonder if treating 1 will migrate to the 2nd eye like some of the other treatments have. I don't know if we should classify eyes as two organs or one at this point. Or none and just lump them in as extrusions of the brain.
If I had to hazard to guess….yes, it would be possible in theory for it to migrate to the other eye. Gene therapies using viruses in the eye are reported to have the ability to transport from one eye to the other. I would say it is possible, but how much? Who knows.
Can't look at the paper right now, but usually to put CRISPR into retinal cells, people use lentivirus (viruses are after all super good at injecting nucleic sequences into cells). From their press release, it sounds like the form of CRISPR they used is probably a base editor. They use a guide sequence that matches the mutated copy of a gene, CEP290, which is responsible for the blindness. The CRISPR system is drawn to the mutation in a cell's DNA by its guide and corrects the mutation. Some cells other than retinal cells are probably affected but this isn't a major problem. The retina is pretty isolated and CRISPR _should_ only edit the defective, mutated copy in any case -- although nothing is perfect and there is always some amount of unintended editing.
This potential therapy is delivered by a virus. You subretinally inject the virus and it is able to go into photoreceptor cells to deliver its genetic payload (which encodes for CRISPR). The expression of the genetic payload has a special sequence (aka a ‘promoter’) in it that should, in theory, only work in eyeball cells, so CRISPR is only expressed in the cell types you want it to be in.
You may not need to target specific types of cells if those genes are only expressed in specific types of cells. That is, full body editing would not affect cells unless those genes are expressed, as long as editing does not change expression.
This is a very credible study by a very good team. It is also based on well established techniques. Several things make this very specific for the target photoreceptors. 1. Subretinal injection: the gene vector is injected directly into the space between the photoreceptors and the retinal pigmented epithelium. This gives the photoreceptors first chance at the vector. 2. The vector is packaged in a virus shell (Adeno-associated virus type 5, AAV5) that has high tropisim (“sticks to”) photoreceptor cells. 3. The vector contains a promoter (genetic “on switch”) that is selective for photoreceptor cells. So even if the virus gets into the retinal pigmented epithelial cells, the payload will not be turned on.
These methods have been used in experimental work for a long time. Nothing really new here. The new part is the selection of patients with a specific kinds of CEP20 defect that might have some surviving but sick photoreceptors. Very rare. The gene defect has already killed most of the cells, but we are looking to rescue survivors. It worked, but only weakly. Just a small cohort (4) of patients showed any rescue and the rescue was small. They are legally blind before and still legally blind after. Just a tiny improvement in visual performance tests. We don’t really know that the gene payload did anything. Improvement can happen from sham injections alone and there were so few patients they couldn’t do that. Good work. Solid reporting. No hype. Phase 1 is a safety check. Phase 2 is efficacy. They have enough to warrant trying again. But not a nuclear breakthrough. Incremental. The necessary steps likely include recruiting younger patients that have more surviving photoreceptors. The problem there is that the vision tests are statistically weaker in preschoolers. Hard work. Eric P is one of the best.
Can't explain it, but if you do podcasts look up radiolab and crispr. They talk about it a lot, and how they can make it pass itself down generation to generation.
Thanks! I have a fairly good understanding of CAS90 and CRISPR and how they work once they're in the cell, but not much about how to use it effectively.
Good news for me, I have (RP) Retinitis pigmentosa. I've been waiting for a cure and hoping to correct my vision loss. Currently, I have 5 to 10% center vision remaining, so there are definitely people worse off. Still would be nice to drive again one day and be able to see properly.
My father in law has this and he is down to 1-2 percent, his brother had it as well. We got his genetic testing done, but it was not a type that had been identified or marked yet. We think his maternal grandmother was a carrier because she was severely visually impaired in her later years. To make it worse he also has CLL and rheumatoid arthritis, as well as osteoarthritis. I really hope they come out with a treatment for him so bare minimum it will slow the progression.
Luckily, my genetic testing found the gene mutation that cause the RP. It was called ushers 2, and most people with that gene mutation are born blind and deaf. They also said I'm more susceptible to other diseases due to the gene mutation. They are finding more gene mutations all the time, so hopefully, they can identify your fathers soon. If this treatment works it should reverse vision loss. 🤞
Abstract
BACKGROUND
CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).
METHODS
We performed a phase 1–2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora–Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire–25 (in adults) or the Children’s Visual Function Questionnaire (in children).
RESULTS
EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.
CONCLUSIONS
The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1–2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.)
———————————
I am not familiar at all with this type of testing, but would it be safe say that this was an extremely cautious test to build up trust in human gene editing?
So when do I get:
Photosynthesis Skin
Cat eyes
Chimpanzee strength
Cancer proof lungs
A bulletproof liver
Immortal shark cells
Super Blood
A tail
And seasonal skin color
Could someone that had lasik get a genetic treatment or would the change in cornea just make you myopic in the opposite direction if you correct the defect?
Welcome to r/science! This is a heavily moderated subreddit in order to keep the discussion on science. However, we recognize that many people want to discuss how they feel the research relates to their own personal lives, so to give people a space to do that, **personal anecdotes are allowed as responses to this comment**. Any anecdotal comments elsewhere in the discussion will be removed and our [normal comment rules]( https://www.reddit.com/r/science/wiki/rules#wiki_comment_rules) apply to all other comments. **Do you have an academic degree?** We can verify your credentials in order to assign user flair indicating your area of expertise. [Click here to apply](https://www.reddit.com/r/science/wiki/flair/#wiki_science_verified_user_program). --- User: u/chrisdh79 Permalink: https://www.nejm.org/doi/10.1056/NEJMoa2309915 --- *I am a bot, and this action was performed automatically. Please [contact the moderators of this subreddit](/message/compose/?to=/r/science) if you have any questions or concerns.*
Well this is incredible. Can someone give me a mid-level explanation of how the medicine gets into the right cells (and the ramifications of the medicine going into cells that do not need it)? Is it simply shoot the medicine, hope the right cells are affected, and if not (later, assuming it is found safe) just inject more until all cells that need corrected have received the gene edit?
You can create constructs that will only be expressed when ~~someone~~ something* else is present in the cell. If you’re injecting into an eye cell, you could make your construct such that it only is turned on when is present. Since eye cell will always express that protein, but testicle will not, you can now see from your eyes instead of your balls.
In CRISPR, it isn’t actually a protein that you target, but a specific DNA sequence that’s targeted with guide RNA.
This guide RNA tells CAS9 protein “hey come here”.
And then old sequence is snipped out and new sequence is inserted.
But dna/protein are closely related so hopefully you get the right kind of idea.
I also might be wrong but this is my understanding
Excellent, that makes sense. Thank you! I didn't know about the ability for it only to activate if something else is present. > Since eye cell will always express that protein, but testicle will not, you can now see from your eyes instead of your balls. Aww, nuts.
Don't be so pessimistic! This just means we need to grow eyes on our balls, the seeing part has already been solved!
I feel inspired! Alright, I'm on it. Should I apply eye cream daily?
I wonder if treating 1 will migrate to the 2nd eye like some of the other treatments have. I don't know if we should classify eyes as two organs or one at this point. Or none and just lump them in as extrusions of the brain.
If I had to hazard to guess….yes, it would be possible in theory for it to migrate to the other eye. Gene therapies using viruses in the eye are reported to have the ability to transport from one eye to the other. I would say it is possible, but how much? Who knows.
Eyeballing your response.
Can't look at the paper right now, but usually to put CRISPR into retinal cells, people use lentivirus (viruses are after all super good at injecting nucleic sequences into cells). From their press release, it sounds like the form of CRISPR they used is probably a base editor. They use a guide sequence that matches the mutated copy of a gene, CEP290, which is responsible for the blindness. The CRISPR system is drawn to the mutation in a cell's DNA by its guide and corrects the mutation. Some cells other than retinal cells are probably affected but this isn't a major problem. The retina is pretty isolated and CRISPR _should_ only edit the defective, mutated copy in any case -- although nothing is perfect and there is always some amount of unintended editing.
Thank you!
This potential therapy is delivered by a virus. You subretinally inject the virus and it is able to go into photoreceptor cells to deliver its genetic payload (which encodes for CRISPR). The expression of the genetic payload has a special sequence (aka a ‘promoter’) in it that should, in theory, only work in eyeball cells, so CRISPR is only expressed in the cell types you want it to be in.
Thank you! I did not know about promoters, that's excellent. We're really going to see some incredible medical science these next few decades.
You may not need to target specific types of cells if those genes are only expressed in specific types of cells. That is, full body editing would not affect cells unless those genes are expressed, as long as editing does not change expression.
This is a very credible study by a very good team. It is also based on well established techniques. Several things make this very specific for the target photoreceptors. 1. Subretinal injection: the gene vector is injected directly into the space between the photoreceptors and the retinal pigmented epithelium. This gives the photoreceptors first chance at the vector. 2. The vector is packaged in a virus shell (Adeno-associated virus type 5, AAV5) that has high tropisim (“sticks to”) photoreceptor cells. 3. The vector contains a promoter (genetic “on switch”) that is selective for photoreceptor cells. So even if the virus gets into the retinal pigmented epithelial cells, the payload will not be turned on. These methods have been used in experimental work for a long time. Nothing really new here. The new part is the selection of patients with a specific kinds of CEP20 defect that might have some surviving but sick photoreceptors. Very rare. The gene defect has already killed most of the cells, but we are looking to rescue survivors. It worked, but only weakly. Just a small cohort (4) of patients showed any rescue and the rescue was small. They are legally blind before and still legally blind after. Just a tiny improvement in visual performance tests. We don’t really know that the gene payload did anything. Improvement can happen from sham injections alone and there were so few patients they couldn’t do that. Good work. Solid reporting. No hype. Phase 1 is a safety check. Phase 2 is efficacy. They have enough to warrant trying again. But not a nuclear breakthrough. Incremental. The necessary steps likely include recruiting younger patients that have more surviving photoreceptors. The problem there is that the vision tests are statistically weaker in preschoolers. Hard work. Eric P is one of the best.
Your reply makes me weak in the knees. Thank you! P.S. Is there a CRISPR treatment for weak knees?
Can't explain it, but if you do podcasts look up radiolab and crispr. They talk about it a lot, and how they can make it pass itself down generation to generation.
Thanks! I have a fairly good understanding of CAS90 and CRISPR and how they work once they're in the cell, but not much about how to use it effectively.
Good news for me, I have (RP) Retinitis pigmentosa. I've been waiting for a cure and hoping to correct my vision loss. Currently, I have 5 to 10% center vision remaining, so there are definitely people worse off. Still would be nice to drive again one day and be able to see properly.
My father in law has this and he is down to 1-2 percent, his brother had it as well. We got his genetic testing done, but it was not a type that had been identified or marked yet. We think his maternal grandmother was a carrier because she was severely visually impaired in her later years. To make it worse he also has CLL and rheumatoid arthritis, as well as osteoarthritis. I really hope they come out with a treatment for him so bare minimum it will slow the progression.
Luckily, my genetic testing found the gene mutation that cause the RP. It was called ushers 2, and most people with that gene mutation are born blind and deaf. They also said I'm more susceptible to other diseases due to the gene mutation. They are finding more gene mutations all the time, so hopefully, they can identify your fathers soon. If this treatment works it should reverse vision loss. 🤞
Abstract BACKGROUND CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant). METHODS We performed a phase 1–2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora–Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire–25 (in adults) or the Children’s Visual Function Questionnaire (in children). RESULTS EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score. CONCLUSIONS The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1–2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.) ——————————— I am not familiar at all with this type of testing, but would it be safe say that this was an extremely cautious test to build up trust in human gene editing?
Could this be done for hair too? 🤔
So when do I get: Photosynthesis Skin Cat eyes Chimpanzee strength Cancer proof lungs A bulletproof liver Immortal shark cells Super Blood A tail And seasonal skin color
cripsr
Could someone that had lasik get a genetic treatment or would the change in cornea just make you myopic in the opposite direction if you correct the defect?
Oh how i wish my dad could be helped by this. He has macular degeneration. Its getting bad
This says inherited blindness and deafness. Would this work for someone who has developed blindness or deafness not from genetics?