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[jay]

Hi Andy,
A question for Bluebird.
Will they release subject's full genome sequence public before and after gene therapy?
Is it the part of their terms and conditions with subjects?
I tried to search if putting such condition in trial agreement is allowed by US law but not successful.

[jay]

So many questions to Andy, please answer anyone,
In addition to my previous post, after seeing David Levy's interview by Josephine, another question to Bluebird.
What is the exact mutation they cure? or do they replace entire HBB?
There are multiple Thalassemia major mutations on HBB.

[Andy Battaglia]

Jay,

I have many urgent matters to deal with on a daily basis, so I must prioritize. Addressing situations that require immediate attention will always take precedence over questions that have no urgency. I hope you do realize that my efforts are volunteer and that I give an inordinate amount of time to thals. I have no appreciation for impatience. Excuse me if my time has been spent on helping people with urgent issues that should have been addressed by their own doctors long ago. I really will put the mother of a 36 year old woman whose life is not worth living above random questions that have absolutely no urgency. In addition to my public work here, I run three Facebook thal groups and am constantly inundated with emails and personal messages. It becomes quite frustrating when adults show a lack of patience. And I say all this while suffering for over two weeks from the flu, yet I have missed no work and have attended to some very urgent cases, in spite of feeling terrible.

To answer the questions, they are doing DNA testing of patients. This is seen in each patient being labeled HbE beta thal +, beta zero zero, beta + zero, etc. They can only know this through testing. The reason for doing this is to show that it works on all patients, regardless of the severity of their thalassemia. The original condition has no relevance in terms of the cure, though. Good beta globin genes are inserted into the body and what is already there has no relevance beyond its initial ability to produce hemoglobin, which in the end will be part of the whole. What trials will show is what has to be done in terms of preparation in terms of chemotherapy, and how dosing has to be adjusted for individual cases. The original genotype has no effect on this process. Unlike with BMT, you are not changing the patients genetically. It is simply insertion of working genes. Their function substitutes for what is already in the body and does not work properly. The old genes are still there and 'working" but a newly introduced beta globin gene will do the work. You can almost look at it as a recipe that needs something. Ah, salt! It's incomplete until salt is added and the blood making ability of thals is incomplete until you add the salt of a working gene and now the recipe works.

[Andy Battaglia]

And Jay, if I have missed any questions with my responses, please point to the posts and I will address therm. I try to catch up on weekends when time permits, and try to find everything I have missed. but sometimes overlook posts.

[jay]

Hi Andy,
I must apologize for sounding urgent, I am not native English, and actually I wanted someone else to answer it because I do understand the extra efforts you put and I am aware of it from long time. This forum has given immense knowledge to me and I couldn't have done better it without this forum. I feel so many questions are directed to you because everybody believes in you. 

[Andy Battaglia]

No problem. Just realize that I am an incredibly busy person even before I get to thal work, so I do have to often put things off until I have more time. My activity on thalpal does normally increase on weekends when I am not at work. Lately, my efforts have been reduced by illness. Hopefully, this lingering flu will soon clear up. I hate to respond to many posts when my mind is not as clear as I wish. If I feel I cannot adequately process thought, I will wait until my head clears up.

[jay]

How gene therapy works? TEDx by a Bluebird guy

https://www.youtube.com/watch?v=Ez560GnkSrE

[jay]

I have been studied biology till age of 19 before moving on to technology, I can do some basic DNA tests, I can do electrophoresis, and I think I understood the explanation in previous post. (These all 'I can's where unnecessary). But again I stuck, pity on me, do this process cause additional mutation in the particular cells? Do this process cause extra addition in genome other that the mutated part? Are there other parts of vector grow along with the cells?

[Andy Battaglia]

No, no mutation is caused. Working beta globin genes are inserted into the patient where they can multiply. The gene vectors are produced in a lab and are not from a donor, so no reactions. To put it simply, something is added that is not already there. It's a normally working gene. The method varies slightly between companies, as only the trial at Sloan Kettering uses the beta globin gene exactly as is found in the human body. The Northstar trial uses a mutated gene, but this causes no mutation in the body, anymore than the mutated gene already present in thals does not cause any mutation of anything else in the body. This is all confined to the beta globin gene. So, instead of relying on a mutation that does not work, they use a mutation that does produce beta globin. This new gene's output can thus be easily monitored and we see the results in the trial reports, as the new hemoglobin being produced is listed as part of the whole in the charts that have been posted. The new hemoglobin produced by the new gene is labeled as HbA t87Q in the charts.

[Sharmin]

Andy,

Thank you kindly for synthesizing this information for us.  I hope that you are starting to feel better!  I was wondering if you had heard anything from Sloan Kettering.

Sharmin

[catchR]

Thanks Andy for making it so easy to understand, we can easily lost on the technicalities.

Hope you have started to feel better!

[jay]

one more, What causes infertility? does it? Why it is suggested to save reproductive cells?

[Sharmin]

Bluebird bio is due to present this weekend.  The stock price has skyrocketed.  This success is so so great to see.  We're are blessed that thalassemia is the disease being cured by this therapy.  So many other ailments wait.  I hope that this will be a huge success and such treatments can be extended to help others.

Jay, the chemotherapy which is used to suppress and ablate the marrow (which is done both to suppress the immune system so that the corrected cells will be accepted and to make room for the corrected marrow to settle in to the patient's body) can also cause damage to reproductive cells.  There is a risk of infertility with this dose of busulfan (the chemotherapy drug utlitized for this procedure).  Storing reproductive cells prior to the treatment can ensure that the patient can have children if the patient becomes infertile after treatment. 

I hope my answer is helpful,

Sharmin

[Andy Battaglia]

I do have a call coming up with Bluebird in the first half of May. We're getting far along enough in the trials where we should have a very good idea of what to expect in terms of both results and quality of life post trial. The next report should also have a follow up on the sickle cell patient. I'm optimistic.

[Parin]

Thanks Andy for sharing the details.

I'm too optimistic.