Turning Blood Red: The Fight for Life in Cooley's Anemia

I am an Emeritus Professor of Medicine at Columbia University and would like to make your members aware of the following events:

The first successful clinical trial of a patient with severe thalassemia has recently been published in the journal Nature on September 16th, 2010 (copy attached). A 21 year old man who required monthly blood transfusions has not required any transfusions for the past two years following the gene therapy procedure. I am a co-author on this paper.

My book, "Turning Blood Red: The Fight for Life in Cooley's Anemia," also describes the clinical trial. In addition, it contains sections on patients and families with the disease; research into the pathophysiology of the disease; and current and future approaches to thalassemia therapy (flyer attached). The book is available on Amazon; Barnes and Noble; Borders; and at World Scientific Publications. A sample chapter is free on the web (attached).

My website: arthurbank.com, describes advances in thalassemia.

I hope you can make your members aware of these activities.

Thank you.

Dr. Bank,

Welcome!  It is such a pleasure to have you here.  I have a copy of your book and it does an amazing job helping people understand this disease.

I wish you the best in your research.  It was such a pleasure meeting you in New York last year - I can't believe it has already been a year!

Thank you for providing these links.  We all wish you and your group the best in finding a cure for thalassemia through gene therapy. 

Best,

Sharmin

Thank you Dr Bank. Our members have been quite excited to read recent news accounts about this publication. Thank you for the entire article. We have long run a poll on this site about what people think should be the top research priorities concerning thalassemia and a gene therapy cure has always been the top response. The continued progress in this field gives hope to all, and the question in the minds of everyone will be changing from "can this work?" to "when will this be reality?" It's a change of words and a change of mindset, but looking at one very important area, this should also lead to a change of funding opportunities for this and other gene therapy research to continue and thrive. The publicity generated by this article should prove to be a powerful tool for persuading potential investors that this is indeed the future.

Thank you and best wishes for the success of this endeavor. Patience will be required, and I hope this gives even more incentive to patients to take care of themselves today, because this will be a reality.

Hi Manal,
what do you thin about this? positive or negative?
I want to know your opinion.

Dr Bank,

Welcome and thank you for joining our site it is an honor to have you here.

Zaini.

Dear Dr Bank,
Kindly I need to know to what extend can current conditioning regimen you are using can affect the candidate for gen therapy?
best regard,
Mohamed 

I am not a doctor or a researcher. However, I am one who has spent many years learning all he could about thalassemia, its treatment and potential cures, and I have some questions regarding this article and its publication in Nature.

Since only about half of all HbE beta thals require transfusion, why was an HbE beta thal chosen as the patient, rather than a thal major (all to almost all thal majors require transfusions)? The patient used appeared to be an intermedia before his first transfusion, with a hemoglobin level of 6-7. I will also note that this patient already showed some ability to produce fetal hemoglobin at an early age.

Why was a mutant gene used? Doesn't this make eventual FDA approval much more difficult? The FDA will already be quite skeptical about anything called gene therapy, so why create a potential for even more problems with approval by using a mutant gene? Does this not in fact, raise the possibility that gene therapy not using mutant genes may suffer a stigma by association and lead to barriers to eventual FDA approval? Along with this question, I must mention that Dr Sadelain's process does not use a mutant gene.

"The percentage of vector-bearing nucleated blood cells (NBCs) increased progressively after transplant and stabilized at ,11%."

It is my understanding that with a bone marrow transplant, a 20% rate of hemoglobin production is required to achieve an Hb level of about 10. This is required to keep a patient transfusion free. How is this 11% success rate significant for true thal majors? It appears to me that without a coinciding high rate of fetal hemoglobin present, that this patient would not be transfusion independent. What is the reason given for the high HbF level? Stopping transfusions raised both the HbF and the HbE. Has this patient been given any fetal hemoglobin inducing drugs like hydroxyurea since the implant? If not, does cessation of transfusion account for 100% of this increase in HbF and if so, doesn't this indicate that the patient was not the equivalent of a thal major? By my calculations, we would still be seeing an Hb level of 6-7% without gene therapy. While an increase of 3-4 per cent in Hb is admirable, it does not appear to be enough to eliminate transfusions for most thal majors.

I would very much like an explanation of why this article has been published, since it seems to provide a false hope for thalassemia majors, and the results are based solely on work with one patient. Wouldn't it have been more prudent in terms of true science to wait until results were available from more than one patient? I have questions about these results and I do not understand why more isn't said about this unusually high HbF level. Most patients would not be able to replicate this level, leaving them transfusion dependent in spite of the gene implant. Isn't the publication of this article premature? Doesn't the publication of this article also raise a question about the promotion of investment in this particular company, which of course will be at the expense of another company that is about to start trials of gene therapy that does not use a mutant gene? Was the timing of the release of this article coincidental or intended to divert investment from one company to another? How can this be good for patients in the long run, if a potentially superior process falls by the wayside due to the premature publication of a study that in my opinion, is presented with a real bias? Yes, there is some evidence that the process works to some extent, but shouldn't we wait until a process exists that offers real hope before we parade the results of this process on one patient, who wasn't even a beta thal major? To a skeptic, it may seem that the main beneficiaries of the release of this article are the same people who have recently sold this process for a large sum of money.

In the end, are we more concerned about a cure or potential profits? Are we selling out the patients to the highest bidder? Why should we trust the company that has purchased this process when it appears they may be very active in trying to squash the competition? How can this be in the interests of the patients?

I have followed this work on gene therapy for many years and although it has always seemed like the best hope for a cure, I cannot believe that we are currently on the right path, with the right path being that which is directed by the best interests of thalassemia patients.

I apologize that I cannot just blindly cheer for these results when those very results raise many questions. I do not want to see patients manipulated into supporting something that will not help them, and until all the questions are answered adequately, I must reserve any celebration.

Declaration: I have no financial interest in any person or company involved in gene therapy or in any manner regarding thalassemia. I am completely a volunteer with no financial interest in this area. I am an advocate for thalassemia patients because it is the right thing to do and not because it will profit me financially in any way.

Dear Andy i took the liberty of mailing arthur bank and qouting all that you have written above.

he wrote this in his reply:

"I just received your e-mail. I have not read the article by Andy Battaglia. Can you e-mail it to me?

I will be happy here to answer your (or Andy's) questions here.

1. The fact that we chose a patient with HbE/beta thalassemia patient is irrelevant to the results we obtained and reported. We chose this patient because we thought he was an ideal candidate. He had required transfusions since an early age and was transfusion dependent-a requirement for the trial. He had a hemoglobin of 6 documented without transfusions. Essentially, he was as severe a patient as most patient's with two beta thalassemia genes, homozygotes for beta thalassemia, patients with Cooley's anemia." who have comparable or lower hemoglobin levels.
It is true that one could label him a "thalassemia intermedia" but only if you are including in that category patients who require transfusions, which usually is not the case. The definition of thalassemia intermedia is relatively vague. Our patient required transfusions every 3-4 weeks to maintain his hemoglobin at a reasonable level, 9-10 gms percent. He had shown his need for transfusions over many years. He was not in the category of hemoglobin E-beta thal patients who are milder and do not require transfusions.

2. The fact that he was producing some fetal hemoglobin is also irrelevant. Patients with two beta thalassemia genes also produce some fetal hemoglobin, but not enough to compensate for their inadequate beta globin production. In our patient, his fetal hemoglobin production and his HbE are certainly contributing to his hemoglobin level, but it is clearly his new hemoglobin produced by our gene therapy that has allowed him to be transfusion-independent and to maintain his hemoglobin at a reasonable, sustainable level over more than two years.

3. A mutated beta globin gene, beta87 (hb87). was used in oir trial in order for us to distinctly and easily distinguish the production of this new hemoglobin resulting from our gene therapy from the normal hemoglobin (HbA) which would be present in the patient from the blood transfusions he was continuing to receive during his recovery period. The "mutant" hemoglobin we used, Hb87, has the same oxygen-carrying capacity as normal HbA so it is really not a "mutant" in any bad sense of the word. It is functionally the same as normal HbA. Although it is possible to distinguish new normal hemoglobin from transfused normal hemoglobin at the RNA level with the vector to be used by Sadelain, it will not be possible to distinguish the actual hemoglobin being made from transfused hemoglobin A, as far as I understand his protocol. Obviously, if his patients no longer require transfusions when they previously did, that would indicate success. But small increases in hemoglobin resulting from gene therapy would be difficult to document clearly if the patient continued to receive transfusions.

4. The amount of new hemoglobin, Hb87, produced has been sufficient to have the patient free of transfusions. The exact mechanisms by which this has occurred are unclear. Certainly, stopping the transfusions has allowed the patient to increase his fetal hemoglobin and HbE since they are no longer suppressed by transfusions. But without the new hemoglobin we provided, the patient would still need transfusions.

5. We do not know what the therapeutic result will be in future patients. Certainly, we will strive for as much new hemoglobin production as we can get. We would hope for even more new hemoglobin production than we have obtained with our first successful patient. Hopefully, it will be enough to make patients with two beta thal genes transfusion independent, at least, and increase their fetal hemoglobin. We will have to wait and see.

6. As far as publication is concerned, we waited three years after this patient and other patients were treated to publish, and five years after the trial in Paris began. We view this publication as a progress report and the first true success of human globin gene therapy. As far as the "timing" of the publication is concerned, it was driven by the results of the trial, and not financing of the trial or its commercial implications. Sadelain has published many papers about his proposed clinical trial without a single data point on any patients. What motivated all of those publications?

I hope this answers your questions and confirms your previous confidence in me in my work in trying to cure thalassemia patients with gene therapy. I will be glad to have you distribute this e-mail to whomever you wish.

And I am sorry if you have been misled in evaluating this work by the arguments of others.

Arthur Bank"

I am often asked to post about a topic by others, as it is recognized that one of my roles is to be a journalist and reporter. My questions here were a direct result of me acting in this role. Because of this, I felt obligated to ask the person who requested that I ask the questions about a response. For the moment, I have been asked to refrain from responding at this time, for reasons having nothing to do with Dr Bank's response. Once again I find myself in the middle of a situation not of my own choosing, but which falls on me because I have the audacity to speak up, a trait also found in my good friend, the late Ashish Vazirani, who proved to be a constant thorn in the side of the thalassemia establishment. Here's to you, Ashish. Ashish was probably the very first online thal journalist and was well known for his blunt, but totally sincere approach. We were regular collaborators on various projects, and I know he would appreciate that I have been willing to not just listen, but also ask questions where needed.


And I would like to remind everyone that I am on the record as saying that this one-patient trial has shown that gene therapy will work. I do have questions and not all were asked in my earlier set of questions, but I do not doubt that this will work, and in fact have long been a proponent of this research. However, each group involved with gene therapy has different methods and there will be questions for all. To not ask would be less than diligent in my duties to patients. When I saw no less than Dr Sadelain asking pointed questions of Dr Leboulch at the 2009 NYC conference about his methods, I know I should do no less when further explanation is required. Please keep in mind that ultimately, the safety and efficacy of gene therapy will have to be absolutely proven before any official approval can ever be given, and the questions asked during the approval process will be far tougher than anything I ask. If anyone feels they have been mislead by the questions, I would submit that you are confusing diligence and criticism. Questions DO need to be asked every step of the way. But please, do not interpret questions as criticism. A good journalist asks questions and hopefully gets a few answers along the way. I constantly have questions for thal doctors and when you get into areas like bone marrow transplants and gene therapy, the lives of patients are at stake and it would be negligent to demand anything less than the best from the doctors. I always appreciate when a doctor does respond and would like to thank Dr Bank for his reply. But, as I said, I do and will always have more questions, because patients and parents will always have more questions.

 I received Andy's comments on the gene therapy trial in Paris by e-mail and responded to them.  I had lost sight of the thalpal.com site and had not seen Andy's comments about the trial and our publication. That's how my recent comments on the site were generated. I will be happy to answer other questions about the Paris gene therapy trial or anything else you think I can clarify, and I will try to keep in touch. Happy holidays to all. Arthur Bank.

Dr Bank,

I do have one question that I imagine is on the minds of most. From what has been seen with this patient, is there a belief that this process can eventually produce a higher output of beta globin? What has been accomplished here is a good first step, but for a beta zero patient, a bigger boost in hemoglobin would be necessary to free the patient from transfusions. Are there things, such as increasing the amount of mobilized stem cells that can be changed that would hopefully bring a significantly higher beta globin output?

I believe that the globin gene therapy trial underway in Paris and those planned by others can produce the amount of hemoglobin necessary to allow patients with beta zero-beta zero thalassemia to become transfusion independent. This goal can be accomplished by increasing the number of gene-expressing stem cells and by increasing the amount of new normal hemoglobin produced in gene corrected red blood cells. 

Hi everyone. I am attaching a copy of a recent review article I wrote on gene therapy for thalassemia in the Hematology/Oncology Clinics of North America.

I also wanted you all to know that my book, "Turning Blood Red: The Fight for Life in Cooley's Anemia," is now available on Amazon Kindle and on your iPad or iPhone through Apple's iMacBook store.

Arthur

Thank you Dr Bank. I have passed on the note about how to buy an E-copy of your book to our group on Facebook.

The summary you have provided is quite interesting and helps to demonstrate the progress being made with each new trial. The key does seem to be introducing enough of the beta globin gene into the patients to cause a large enough increase in beta globin production to free patients from transfusions. Recent progress in stem cell mobilization will prove to be quite significant for this process.

Dr Bank, do you feel that this same process can eventually be used to treat other genetic disorders? And if so, do you see this as one of the biggest developments in medicine ever?

I'd like to join your group on Facebook, but couldn't find thalplal or you. Help!

Gene therapy is being used in several other diseases. Patients with subacute combined immunodeficiency (X-SCID) and adenosine deaminase deficiency (ADA deficiency) have been cured by gene therapy. In these diseases, relatively low levels of corrective gene expression lead to preferential survival of of gene-corrected cells. Patients with adrenoleukodystrophy (a neurologic condition), chronic granulomatous disease (a white blood cell disease). hemophilia, and Wiskott-Aldrich syndrome (a platelet disorder) have all been treated with gene therapy as well.

As far as your question about the role of gene therapy in medicine long-term is concerned, I would say that remains to be determined in the future.