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.
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.”
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.
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 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.