Meeting Dr Malech
(Susan Walsh writes):
Dr Harry Malech caused quite a stir in the world of gene therapy (GT) and CGD in 1997 when he reported on the results of the first GT trials for CGD. I had the great pleasure of meeting this pioneer of CGD research and gene therapy at the National Institutes of Health where he leads the Genetic Immunotherapy Section. Our meeting coincided with treatment of a second adult X-CGD patient recruited to his current GT trial!
Dr Malech has a history of making major advances in CGD. He identified and cloned the p47phox and p67phox genes that are affected in two genetic forms of CGD. He carried out the first proof of principle experiments developing retrovirus vectors encoding each of the four CGD genes and showed that these gene delivery vectors can achieve functional correction of CGD in the test tube. His first GT trials for CGD in the mid1990’s enrolled ten CGD patients, five with X-linked CGD and five with the autosomal recessive p47phox deficient form of CGD. “In these early trials we detected oxidase activity in white blood cells from each patient for an average of three months after the gene-corrected stem cells were transfused," explained Dr. Malech. "In one patient, phox activity was still present six months after transfusion. On average, the corrective gene was present in one out of every 5,000 cells. While the numbers of gene-corrected cells were small, the study demonstrated unequivocally that gene therapy of stem cells can produce functionally normal blood cells in patients for a prolonged period. Recent clinical trials have built on these results and shown that even short-to medium-term production of oxidase-positive cells may be clinically beneficial.” Dr Malech is also working on advancing GT for X-linked severe combined immune deficiency (XSCID), and leukocyte adhesion deficiency (LAD) and working out how the risks of chronic graft versus host disease can be reduced in bone marrow transplantation.
The first CGD trial also established some of the techniques that are still used for the efficient manipulation of patients’ stem cells in GT procedures. These included the use of cell culture media containing no non-human proteins and a closed system of gas-permeable flexible plastic containers for culture and gene transfer. "To our knowledge, this was the first human gene therapy trial targeting stem cells in which animal proteins were eliminated and stem cells were grown in sealed gas-permeable flexible plastic containers," said Dr. Malech. "We showed that it is possible to incorporate these safety features without compromising stem cell viability or gene transfer efficiency. These methods are still used today".
Dr Malech’s latest clinical GT trial for X-linked CGD started almost 8 months ago with treatment of a 28-year-old man with X-CGD. The results were presented in late May at the 10th American Society for Gene Therapy meeting in Seattle. He explains, “Using the vector from our original X-linked CGD gene therapy trial, we have now altered our protocol to concentrate the vector and to give our patients a mild bone marrow conditioning treatment using a drug called busulfan. This will increase the chances of the gene corrected cells to engraft in the bone marrow. The use of busulfan is similar to the approach used in the recent CGD gene therapy studies in Germany. The man we treated was in bad shape. He had large liver abscesses accounting for 55% of the tissue and these were unresponsive to antibiotics. The surgeons were not happy to operate and so GT was put forward as the only remaining option”. Eight months on and the clinical benefit is remarkable with a massive reduction in liver abscesses. However, gene marking has dropped from 25% to 1.1%. “ But those circulating neutrophils that are gene marked express fully normal levels of superoxide activity per cell and if this level is maintained then it may indicate that we have hit the long-term repopulating cells (cells that are not quite stem cells but can give rise to neutrophils over long periods of time) and that the treatment will be beneficial over a long period of time”.
“ What is remarkable is how few oxidase normal neutrophils we need in the circulation to restore to help treat a severe infection in CGD. We have clearly achieved clinical benefit in the treatment of an otherwise incurable infection. The next phase for us and other researchers in the CGD gene therapy scientific community is to determine the additional improvements required to for GT to provide a permanent cure”.
So says Dr Donald Kohn of the University of Southern California Keck School of Medicine in the July edition of the journal ‘Blood’. In his commentary he mentions the clear-cut clinical benefits obtained in recent clinical gene therapy (GT) trials for young adults with CGD and in infants with X-SCID and adenosine deaminase (ADA)-deficient SCID. “Thus, the debate over gene therapy has moved from ‘will it ever be beneficial?’ to ‘when is it beneficial?’ The article was written in response to results where GT was used for three young adolescents with X-SCID for whom prior attempts at allogeneic BMT* had failed to result in a functioning immune system. The work suggests that gene therapy could be used as a salvage treatment for older X-SCID patients who are in a desperate clinical situation rather than additional attempts at further BMT procedures where graft versus host disease could occur or worsen.
*An allogeneic transplant uses bone marrow or stem cells from a donor whose tissue closely matches that of the person receiving the transplant. This may use bone marrow from a sibling or other relative or a closely matched, non-related donor.
LinkIMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2007 The Chronic Granulomatous Disorder (CGD) Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
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