Genetic therapy cures thalassaemia

This article came in today's(16-09-2010) in a leading News paper (The Hindu) in India.Though it looks promising there are a few hiccups that cannot be overlooked.I have cut and paste the article from the e-copy of the News . 

Genetic therapy cures thalassaemia

TREATMENT: Frequent blood transfusion is needed to treat anaemia in patients with thalassaemia. 

Nearly 10,000 children born every year in India suffer from thalassaemia major, an inherited disease that is caused by an abnormality in haemoglobin (an oxygen-carrying protein) production. This results in ineffective production of red blood cells, thus causing anaemia. This necessitates regular blood transfusion. It not only affects the quality of life of children but also cuts short their life span.

A paper published online in Nature today (Sept 16) reports the first case where gene therapy on an 18-year-old teenager has successfully cured the disease.

Transfusion free 

The therapy was performed three years ago in June and the person has not required any blood transfusion since June 2008, a year after the transplantation was conducted. However, the patient remains mildly anaemic. The frequency of transfusion requirements was 2-3 red blood packs given once a month before the therapy.

“At present, approximately three years post-transplantation, the biological and clinical evolution is remarkable, and the patient's quality of life is good,” note the authors.

Since no red blood transfusion was required since June 2008, the authors consider this case as a “clinical success.”


The procedure 

First the patient's diseased haematopoietic stem cells taken from the bone marrow were separated. They then transferred a functional beta-globin gene capable of producing red blood cells into the haematopoietic stem cells. The beta-globin gene was introduced into the patient's haematopoietic stem cells using a viral vector (HIV-derived lentiviral vector).

With the gene successfully transferred, the patient was subjected to a high dose of chemotherapy before transplanting the genetically modified haematopoietic stem cells. High dose chemotherapy treatment ensured that all diseased stem cells were destroyed. This ensured that the effects of the genetically modified stem cells introduced were not diluted and hence the outcome not compromised.

Destroying the diseased stem cells through chemotherapy prior to undertaking bone marrow transplantation to treat thalassaemia patients is routine.

Following the treatment, the haematopoietic stem cells containing the modified gene started to produce healthy blood cells.

According to a News and Views piece in the same issue of Nature, the levels of genetically modified cells rose from less than 2 per cent in the first few months to 11 per cent at 33 months after transplantation.

Need for caution 

However, there is great need for caution. The genetically modified stem cells appear to have altered the expression of a gene that controls the behaviour of blood stem cells, causing a mild, benign expansion of these cells.

While the effect seen in the patient may be responsible for much of the therapeutic benefit, the possibility that the behaviour is a prelude to cancer cannot be completely ruled out.

The paper notes that the increased levels of a particular protein (HMGA2) that is implicated as a potential cancer stimulus was present in only half of all the haematopoietic cells circulating in the patient's blood.

Based on this fact, the authors note that “there is no evidence of a malignant or pre-malignant state” in the patient.


Earlier experiments 

It must be remembered that earlier experiments of introducing genetically modified haematopoietic stem cells led to cancer. The first time it was tested about ten years ago, a murine leukaemia virus vector was used. Several patients developed cancer.

In a later trial, a retroviral vector was used to introduce the genetically modified beta-globin gene. But the result was the same — patients developed cancer.

Though HIV-derived lentiviral vector was used in this case, there has been some benign proliferation of cells that have a protein which is often implicated in cancer.

Hence many more trials and more investigations are required before genetic therapy for curing thalassaemia can be considered as a viable alternative.



The advantage 

The advantage with genetic therapy is that the therapeutic gene (beta-globin gene) is made in the laboratory and inserted into the vector and transplanted into the body.

This makes redundant the need to look out for a donor, leave alone donors with a perfect tissue match as the recipient's, as is the case with bone marrow transplantation.

Though stem cells harvested from cord blood do not require perfect tissue match, a perfect tissue match, nevertheless, vastly improves the chances of the transplant's success.

Andy ,what will be the possible side effects of Chemotherapy in Genetherapy treatment?Is not chemotherapy considered harmful?Chemotherapy does have long lasting effect like destruction of fertile eggs in female and the same in male too.It has its own short term and long term side effects.Am i correct? Can you throw some light on the same.

Thank you.

Hi samyuktha,

This is one of the biggest differences between this group that has had the one mildly successful gene therapy done, and the group that is about to begin, hopefully by October's end. Sadelain's group uses a milder chemotherapy preparation than the group headed by the French doctor, and this is a point of much disagreement between the two groups. I fall firmly in Sadelain's camp, and agree that if this is to be truly successful, as little damage as possible has to be done by chemo. These are human patients wishing normal lives and this has to always be remembered. Just as we are now seeing with the approach to bone marrow transplants, I believe that in the long run, the gene therapy that uses as little chemo as possible, will be the preferred method.

Hi andy
Wht is differences between gene therpay and BMT ....?
We use chemotherapy in gene therapy and BMT so wht is differences between this ........?

Bone marrow transplant requires transplanting bone marrow or harvested stem cells from one person into another. Less than 1/3 of thals have a matching donor. Chemo is used to destroy the bone marrow of the donor, so that the new marrow can replace it. If the BMT works, then the new bone marrow is producing normal hemoglobin as it should, from the donor's marrow.
With gene therapy, working beta globin genes are inserted into stem cells that were harvested from the recipient and then put back into the recipient. The good beta globin genes will then produce normal beta globin. There is no possibility of rejection as there is with BMT, so there is no host versus graft disease. Gene therapy would also be possible for most thals.

Both procedures require chemo to work and in both cases, there are doctors who have found that using a less harsh mix of chemo produced better results in terms of side effects from the process. Dr Krishnamurti in Pittsburgh has been a pioneer in using less harsh chemo regimens for BMT and Dr Sadelain's group have been pioneers in finding less harsh chemo to use in gene therapy.

Thanks Andy for giving such information. I am waiting for the Day when Dr. Sadelain's gives every thal a GREAT NEWS.....

But i still have a doubt why there is need of chemo in Gene therapy as new b-globin gene going to alter all the cell.....i can understand the case of BMT

I'll quote from the above article, which explains why chemo is needed for gene therapy.

With the gene successfully transferred, the patient was subjected to a high dose of chemotherapy before transplanting the genetically modified haematopoietic stem cells. High dose chemotherapy treatment ensured that all diseased stem cells were destroyed. This ensured that the effects of the genetically modified stem cells introduced were not diluted and hence the outcome not compromised.

I found this article in outre local paper. http://epaper.orlandosentinel.com/OS/OS/2010/09/23/ArticleHtmls/23_09_2010_002_003.shtml

Andy,
In saying "There is no possibility of rejection as there is with BMT, so there is no host versus graft disease", are you saying even if there is a perfect bone marrow match for my child (he has 3 other siblings), gene therapy would be a preferred method of cure?

"Both procedures require chemo to work and in both cases, there are doctors who have found that using a less harsh mix of chemo produced better results in terms of side effects from the process. Dr Krishnamurti in Pittsburgh has been a pioneer in using less harsh chemo regimens for BMT and Dr Sadelain's group have been pioneers in finding less harsh chemo to use in gene therapy"-
Logically, for Thal Major, there's only 1 defective gene, as oppose to other reasons why one would require a stem cell transplant for cancer. That's my logical deduction (?)

Syaida,

It isn't yet possible to compare BMT and gene therapy because BMT is a reality and gene therapy is in development and won't be perfected for some years. There are two issues with gene therapy that have to be resolved. One is controlling it so that it doesn't grow out of control and cause tumors. Second, it has to sustain. If the effect doesn't last permanently, its value will be lessened.
But, the hopes are it will work and if this does work as hoped, it would have less risk than BMT. However, decisions have to be made in the real world, so until we know more about the successes of gene therapy, it's difficult to consider it as an option to BMT.

What has been happening in BMT with chemotherapy, is that some doctors have discovered that the regimens being used were not totally necessary. Refining the chemo reduces the side effects and makes it easier on the patient. The comparison between stem cells for cancer and for thalassemia is that in both cases, the patients bone marrow is destroyed and replaced. In both cases, the bone marrow is not functioning properly, so it is replaced with stems cells that do work properly.