Promising First Results for Gene Therapy


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The results of the first phase of a gene therapy trial on three adults with Gauchers disease were revealed by Professor John Barranger at a meeting on Sunday 19 April at the NYU Medical Center in New York City. Susan Lewis reports:

Prof Barranger opened his talk on gene therapy by saying that he did not yet know if gene therapy would work but the first phase of his trial showed that the gene for glucocerebrosidase had been success-fully transferred into three patients and was safely producing the enzyme.

The three patients, one woman and two men around 50 years old, continued to have substantial bone disease despite receiving enzyme replacement therapy for a number of years.

After receiving four gene transfers at three month intervals, one patient continued producing enough enzyme to enable Cerezyme enzyme replacement therapy to be stopped in October 1997. Prior to that, the dose was reduced from 60u/k/bw (units per kilogram of bodyweight) to 3u/k/bw over a 12 month period.

Prof Barranger reported that the patient is producing three-quarters of normal enzyme activity, the equivalent to that of a healthy carrier, and remains well.

The second patient also received four gene transfers. Although his enzyme activity did rise, he has subsequently received another three gene transfers. He remains on enzyme replacement therapy.

The third patient stopped taking part in the trial, after receiving two gene transfers, due to adverse effects from an additional drug (Neupogen) needed in the process. However his raised enzyme activity has continued.

Prof Barranger explained that for gene therapy to work, the gene has to be put into primitive non-specialised cells in a patientµs bone marrow called stem cells. It is these stem cells which generate all blood cells including red and white cells. The stem cells also produce monocytes which become macrophages, the cells which donµt work properly in Gauchers disease and therefore accumulate the fatty substance (glucocerebroside) in the liver, spleen and bone marrow.

A small percentage of CD34 cells are stem cells and these can be collect-ed from a patient by taking blood in the usual way from a vein in the arm.

But first the drug Neupogen is given to a patient to stimulate the release of these CD34 cells. The drug, which is taken over a period of five days, can cause a small amount of bone pain, headache and nausea but these symptoms go away once the drug is stopped. Occasionally the drug can lower a patientµs platelet count and it is because of this last side effect that the third patient described above stopped participating in the trial.

As blood is taken from the patient, the CD34 cells are extracted and the rest of the blood returned to the patient.

During a complex procedure involving many different processes, the cells are put into a plastic bag, with a retroviral vector which contains and carries the unchanged glucocerebrosidase gene, and are spun in a centrifuge. The cells are then harvested (collected) and returned to the patient by infusion into the vein.

First Results

Prof Barranger explained that the first phase of the trial was to see if there was any risk to the patient, not to see if there was any benefit.

He and his team have shown that the drug Neupogan can stimulate the release of CD34 cells, that the cells can be collected from the patientµs blood and that 20-30% of the stem cells take up the gene.

They have also shown that the gene can be re-introduced into the bone marrow via infusion into the blood stream. This can be done without having to destroy the patientµs bone marrow first (which has to done in a normal bone marrow transplant using a donor).

For all three patients, they have been able to measure that their gluco-cerebrosidase activity is higher than it was prior to gene transfer.

Prof Barranger said that the three patients had different genotypes (N370/N370, N370/not known; L444P/not unknown) but this had shown no difference in response.

How Many Years Away?

Prof Barranger said the next stage was to recruit more patients. He had sufficient volunteers but the studies remained expensive due to the materials needed to purify the CD34 cells.

He could not start children on gene therapy yet as he still did not have enough information on safety and other issues.

He said he did not know how many transfers will be sufficient to provide a cure for Gauchers disease. It might be one, many or it might never work.

If I had 1½ million dollars and could study 10 patients, I could have reasonable data in two years. I may find I can reproduce my results or I may find I cannot.

If there were no side effects and a clinical response, gene therapy might be possible 12-15 months after that.

We have delayed further studies because of the possibility of a new vector to carry the gene. We will soon know if we proceed with the current one. However if the new vector is better, we will wait for FDA approval to use it.

Over 1,500 patients have used retroviral vectors in different treatments and there is no evidence that these can cause cancers.

We are also performing tests to increase the take up of the CD34 cells into the bone marrow stem cells.'

Other Research

Prof Barranger is also carrying out research into placing the gene into muscle cells to see if they can make the enzyme and deliver it to the bone marrow, liver and spleen.

Prof Barranger stressed Gene therapy may never work or it may work in a few years. Two other studies on gene therapy for Gauchers disease in the USA have closed. We remain the only centre in the USA carrying out a trial on gene therapy for Gauchers disease.


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Source: Gauchers News July 1998

© Copyright Gauchers Association 1998