Ataluren data!
This is for the naysayers! Jill you were right! :)
http://ptct.client.shareholder.com/releasedetail.cfm?ReleaseID=518941
Replies to This Discussion
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Permalink Reply by Tamara Walters on
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Will exon skipping work for premature stop codons/nonsense mutations ? This seems like a dumb question after being well-involved in Duchenne research, but I am still not sure ? Anyone know the answer to this ?
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Permalink Reply by Dave Kramer on
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Don't worry, there are no dumb questions, Tamara. I think the answer ought be: quite possibly. The idea is to bypass the exon where the mutation lives, creating a shorter, but hopefully functional form of dystrophin. This is theoretically an approach that'd address quite a number of the mutation types, including nonsense mutations.
There may be a hitch for our sons here, though. As far as I've been able to tell, if the body has never produced dystrophin (which might be the case for nonsense-mutations) - the body might not recognize this new shortened dystrophin protein as normal and might essentially attack it (re: immune response) thereby degrading or negating the benefit. There's a lot of immunological work being done here that goes way over my head.
-Dave
Tamara Walters said:Will exon skipping work for premature stop codons/nonsense mutations ? This seems like a dumb question after being well-involved in Duchenne research, but I am still not sure ? Anyone know the answer to this ?
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Permalink Reply by Ofelia Marin on
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To date, both Prosensa and AVI report no immune response observed in their exon 51 skipping trials. My understanding is that there quite a debate b/w some of the scientists in the field regarding this subject. I am very curious to see what happens in the next AVI trial starting in Columbus, OH. Dr. Mendell, who published the paper about immune response to dystrophin seen in his gene therapy trial, will be involved in the AVI trial so will get more answers then.
Dave Kramer said:Don't worry, there are no dumb questions, Tamara. I think the answer ought be: quite possibly. The idea is to bypass the exon where the mutation lives, creating a shorter, but hopefully functional form of dystrophin. This is theoretically an approach that'd address quite a number of the mutation types, including nonsense mutations.
There may be a hitch for our sons here, though. As far as I've been able to tell, if the body has never produced dystrophin (which might be the case for nonsense-mutations) - the body might not recognize this new shortened dystrophin protein as normal and might essentially attack it (re: immune response) thereby degrading or negating the benefit. There's a lot of immunological work being done here that goes way over my head.
-Dave
Tamara Walters said:Will exon skipping work for premature stop codons/nonsense mutations ? This seems like a dumb question after being well-involved in Duchenne research, but I am still not sure ? Anyone know the answer to this ?
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"In the study, treatment with AVI-4658 also appeared to have a favorable impact on immunological and inflammatory markers. Restoration of dystrophin was followed by an absence of anti-dystrophin antibodies, suggesting no immunologic reaction to the newly produced dystrophin. There was also an overall reduction in T cell infiltration and inflammatory markers, including CD3, CD4 and CD8 cell counts, in the patient muscle biopsies from the top two cohorts."
http://www.cureduchenne.org/2010/10/avi-biopharmas-investigational-...
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Thanks. I understand exon skipping as a way to "patch" a deletion, but since we are dealing with point mutations as opposed to deletions, I do not know for sure...
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Permalink Reply by Felix Güthe on
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If you are able to skip the whole exon the error being the false stop codon should just be skipped . So in principle - to my understanding- exon skipping can also work for this cases if the Exon can be skipped safely.
Tamara Walters said:Thanks. I understand exon skipping as a way to "patch" a deletion, but since we are dealing with point mutations as opposed to deletions, I do not know for sure...
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Multi-exon skipping might be required in many cases since the reading frame needs to be preserved after the exon containing the point mutation is skipped.
Felix Güthe said:If you are able to skip the whole exon the error being the false stop codon should just be skipped . So in principle - to my understanding- exon skipping can also work for this cases if the Exon can be skipped safely.
Tamara Walters said:Thanks. I understand exon skipping as a way to "patch" a deletion, but since we are dealing with point mutations as opposed to deletions, I do not know for sure...
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Permalink Reply by Jonathan on
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Ok in a nutshell exon skipping does work for non-sense mutations as it removes the stop codon from the sequence. However for the exon skip to work there are a number of factors involved.
- The location of the non-sense mutation. This is important as if it is in the wrong place it can interfer with the splicing motifs or whatever they are called.
- The exon you want skipped and how it fits into the exon after and before it. In a lot of cases it will be a straight single exon skip, but in some cases it may take more than one exon to be skipped to join up the exons after the splicing. I used to have an order which showed how the exons fitted into each other ( ie 1> >2 > >34| |5 ) etc, but I dont know where to find it now.
The problem then becomes actually getting someone to make the compound to skip a specific exon as they are only concentrating on the groups where it will benifit the most people as it gives them the most data for trials which is understandable however still frustarting.
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My understanding on the exon skipping is that the initial trials are being done around exons 48-52, but once that is proven successful, they should be able to "reconfigure" the substance to individual exons, etc.
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Permalink Reply by lisa burke on
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My understanding is that all the other compounds HAVE now been created in the lab (Steve Wilton's been working on this I believe).
Jonathan said:Ok in a nutshell exon skipping does work for non-sense mutations as it removes the stop codon from the sequence. However for the exon skip to work there are a number of factors involved.
- The location of the non-sense mutation. This is important as if it is in the wrong place it can interfer with the splicing motifs or whatever they are called.
- The exon you want skipped and how it fits into the exon after and before it. In a lot of cases it will be a straight single exon skip, but in some cases it may take more than one exon to be skipped to join up the exons after the splicing. I used to have an order which showed how the exons fitted into each other ( ie 1> >2 > >34| |5 ) etc, but I dont know where to find it now.
The problem then becomes actually getting someone to make the compound to skip a specific exon as they are only concentrating on the groups where it will benifit the most people as it gives them the most data for trials which is understandable however still frustarting.
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Hi Lisa,
Do you know if any of the current lines of research involves multiple exon skipping to address a point mutation in exon 7 (seven)?
Regards
Bernardo
lisa burke said:My understanding is that all the other compounds HAVE now been created in the lab (Steve Wilton's been working on this I believe).
Jonathan said:Ok in a nutshell exon skipping does work for non-sense mutations as it removes the stop codon from the sequence. However for the exon skip to work there are a number of factors involved.
- The location of the non-sense mutation. This is important as if it is in the wrong place it can interfer with the splicing motifs or whatever they are called.
- The exon you want skipped and how it fits into the exon after and before it. In a lot of cases it will be a straight single exon skip, but in some cases it may take more than one exon to be skipped to join up the exons after the splicing. I used to have an order which showed how the exons fitted into each other ( ie 1> >2 > >34| |5 ) etc, but I dont know where to find it now.
The problem then becomes actually getting someone to make the compound to skip a specific exon as they are only concentrating on the groups where it will benifit the most people as it gives them the most data for trials which is understandable however still frustarting.
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Permalink Reply by RAKTIM SINGH on
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Hi,
I am aware that DR Matthhew Wood at MDEX is working at oligo optimization project. This involves multi-exon skipping also ( apart from handling on how to deliver oligo much efficiently/how to deliver to whole body etc).
As such multi-exon skipping can be as simple as combining 2-3 required oligo and delivering. But the challange can come with respect to toxicity, efficient delivery etc.
Different experts have different opinions.I guess Dr Wood is trying to prepare other tools (single oligonucleotides) that could allow skipping of more exons.
Raktim
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