Did anyone else see this article?  I am not sure what to think about it or if I am interpreting it correctly. I agree with the article that it may give us insight to the workings of DMD, but what does it mean in regards to future trials?? I would love some discussion on this to help me understand!

 

http://www.medpagetoday.com/Neurology/GeneralNeurology/22599

 

 

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It's a little over my head, but appears to say that some boys have an immune response to dystrophin that defeated the gene therapy. Has to make you wonder what that means for exon skipping.

Would like to hear Sharon or Ofelia talk about this one.
Keith, that was my thought. If we are trying to produce a dystrophin or mini dystrophin, will it work???? How does this affect utrophin??? The article just made my head question and spin all at once....not pretty!!!!



Keith Van Houten said:
It's a little over my head, but appears to say that some boys have an immune response to dystrophin that defeated the gene therapy. Has to make you wonder what that means for exon skipping.

Would like to hear Sharon or Ofelia talk about this one.
Good questions and although I'm not happy about the findings in this article, thanks for bringing it out Lori.

Kinda sounds like the more info about dystrophin & DMD the better. Maybe this finding won't have an affect on exon skipping trials or myostatin inhibitors since I suppose there would have been some info out already about that the immune responsees already. Sounds like some patients are not able to tolerate increased dystrophin, actually fight it off, and this can be determined by a blood test. Too early to speculate re:stem cell therapy. From what I can tell the gene therapy approach is at risk for immune responses because this approach isn't reprogramming the DNA to have the body make new dystrophin but inserting some (from the lab?) instead.

Sounds like another major hurddle scientists must overcome, ugh!
This is the NEJM article published today.
Attachments:
My read is that when the trial failed to produce dystrophin they then went back to identify a reason and found the t-cell immunity issue. Wearas the exon skipping trials to date have both resultedd in increased dystrophin in what appears to be a dose dependent manner.

It appears that the issue applys to gene replacement only.

It may very well be that there are boys who have the existing t-cell problem prior to treatment which may explain reduced results in an exon skipping trial in which case a plan to deal with the t-cell issue prior to or during exon skipping treatment may be helpfull.
In the NEJM article it does mention an immune repsonse in one boy after administration of gentamicin. Isn't that what Ataluren is essentially? It would be interesting to hear what PTC have to comment about their findings.

Also, I don't get why, if there was an immune response seen in two of the boys BEFORE treatment - possibly due to revertant fibres producing some dystrophin - why doesn't that happen in Becker cases where individuals produce even more dystrophin? Or those classed as outliers?

Seem to be so many unanswered questions again...............




Ofelia Marin said:
Actually, the Ataluren trial should be the one shedding more light into this. They had a large enough number of boys in that trial to see if there is immune response against dystrophin and if some of the boys had immune reactivity before they were dosed. Does anyone know if any immune response was reported in that trial? How great will it be if PTC reports more data so anyone else in the community can learn from their trial? Sharon?

It comes as no suprise to me to see immune response in the gene therapy trial, but they hint that it is not the gene therapy and the immune response against dystrophin should be seen with all treatments producing dystrophin. Did I get that right?


lisa burke said:
In the NEJM article it does mention an immune repsonse in one boy after administration of gentamicin. Isn't that what Ataluren is essentially? It would be interesting to hear what PTC have to comment about their findings.

Also, I don't get why, if there was an immune response seen in two of the boys BEFORE treatment - possibly due to revertant fibres producing some dystrophin - why doesn't that happen in Becker cases where individuals produce even more dystrophin? Or those classed as outliers?

Seem to be so many unanswered questions again...............




Ofelia Marin said:
Actually, the Ataluren trial should be the one shedding more light into this. They had a large enough number of boys in that trial to see if there is immune response against dystrophin and if some of the boys had immune reactivity before they were dosed. Does anyone know if any immune response was reported in that trial? How great will it be if PTC reports more data so anyone else in the community can learn from their trial? Sharon?

It comes as no suprise to me to see immune response in the gene therapy trial, but they hint that it is not the gene therapy and the immune response against dystrophin should be seen with all treatments producing dystrophin. Did I get that right?


bob koch said:


lisa burke said:
In the NEJM article it does mention an immune repsonse in one boy after administration of gentamicin. Isn't that what Ataluren is essentially? It would be interesting to hear what PTC have to comment about their findings.

Also, I don't get why, if there was an immune response seen in two of the boys BEFORE treatment - possibly due to revertant fibres producing some dystrophin - why doesn't that happen in Becker cases where individuals produce even more dystrophin? Or those classed as outliers?

Seem to be so many unanswered questions again...............




Ofelia Marin said:
Actually, the Ataluren trial should be the one shedding more light into this. They had a large enough number of boys in that trial to see if there is immune response against dystrophin and if some of the boys had immune reactivity before they were dosed. Does anyone know if any immune response was reported in that trial? How great will it be if PTC reports more data so anyone else in the community can learn from their trial? Sharon?

It comes as no suprise to me to see immune response in the gene therapy trial, but they hint that it is not the gene therapy and the immune response against dystrophin should be seen with all treatments producing dystrophin. Did I get that right?

My read is that they are concerned about two things. One is that each person should be tested for an existing t-cell activity prior to treatment and then t-cell activity following treatment.

Two things stand out. One is that the Prosensa and avii trials to date have reported increased dystrophin production, while Prosensa has not published all of their findings to make them public, AVII has reported what appears to be safe increased production of dystrophin in a dose dependent manner. Their final findings to be reported now at any time; likely during a formal presentation at a conference.

To me it makes sense to test for t-cell activity prior to treatment and then what impact; if any, following Exon skipping, as to date there does appear to be some inconsistent results at lower dosage levels. It does make sense that every child is unique and scientists will need to determine specifically what those unique features are.

There appears to be many improvements needing to be created; including something other than the 6 minute walk test to determine effectiveness. But all and all, things are very exciting to date,
and my belief is that the future will only serve to increase that excitement.
Does anyone know if Prosensa and/or AVI screened for this reactivity to dystrophin BEFORE their trials and included only boys who do not have it? It is the first time I hear that this can exist in some boys before treatment...I expected to see immune response in gene therapy trials producing dystrophin AFTER treatment.
I asked Annemieke and she was very nice to reply:

Dear Ofelia,

Prosensa and AVI did not screen for this immune reactivity before the trial, so boys were not preselected for the absense of this response.
Both have looked at an immune response after treatment and did not find it yet - while they did see dystrophin.
Hopefully this immune reactivity will thus not be an issue for exon skipping, but AVI and Prosensa will carefully monitor this in all patients in the trial.

Best regards
Annemieke
Its been known that self splicing occurs and creates revertenant fibers. I think the depth of the immune response is not completely known. Usually anything that is non-self is seen as an antigen and the body is set up to remove that antigen. However at what level is something considered to be non-self? Gene level or protein level?
The article shows that an immune response in some boys has occured to the revertenant fibers, creating the memory T-cells. It also showed that the gene therapy created proteins that were seen to be non-self and so were removed.
In the end this is valuable information and is something that can be put to good use in further trials in this field. It just means that the body needs to be immunosuppressed to stop the removal of the new mini-dystrophin before they can go forward.
Whats really interesting, is that if the revertanant fibers, and new mini-dystrophin (both of which are just proteins) has initiated an immune response, why hasnt there been similar responses in the exon skipping, and read through approaches?
Yes, that was our question, why none was seen yet in the exon skipping trials. Sharon can give more details about this. My understanding is that they used different assays to measure for "immune response" in the exon skipping trials. They did not use the same assays used to measure immune response in the mini-dystrophin and gentamicin trials Dr. Mendell conducted.



Jonathan said:
Its been known that self splicing occurs and creates revertenant fibers. I think the depth of the immune response is not completely known. Usually anything that is non-self is seen as an antigen and the body is set up to remove that antigen. However at what level is something considered to be non-self? Gene level or protein level?
The article shows that an immune response in some boys has occured to the revertenant fibers, creating the memory T-cells. It also showed that the gene therapy created proteins that were seen to be non-self and so were removed.
In the end this is valuable information and is something that can be put to good use in further trials in this field. It just means that the body needs to be immunosuppressed to stop the removal of the new mini-dystrophin before they can go forward.
Whats really interesting, is that if the revertanant fibers, and new mini-dystrophin (both of which are just proteins) has initiated an immune response, why hasnt there been similar responses in the exon skipping, and read through approaches?

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