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Workshop on Prospects for Gene Therapy of Inherited Phagocyte Disorders

Seattle, WA
May 28-29, 1998

Summary and Recommendations


Summary and Recommendations

The National Institute of Allergy and Infectious Diseases and The National Institutes of Health Office of Rare Diseases convened a workshop on the Prospects For Gene Therapy of Inherited Phagocyte Disorders on May 28 and 29, 1998 in Seattle, WA. This workshop was held in conjunction with the first meeting of the American Society of Gene Therapy. The inherited phagocyte disorders are a group of rare diseases (including Chronic Granulomatous Disease, Leukocyte Adhesion Deficiency, Chediak-Higashi Syndrome, and Interferon Gamma Receptor Deficiency) caused by genetic defects in white blood cells called phagocytes which result in a decreased ability to engulf and kill infectious agents. In Wiskott-Aldrich syndrome both lymphocytes and phagocytes are affected by the genetic defect. The decreased ability to destroy infectious pathogens results in severe, recurrent, and/or life-threatening infections in affected individuals. The workshop brought together a group of distinguished scientists (Appendix) to consider the currently available information and to make recommendations as to the most important and fruitful research opportunities and approaches that are needed in order to develop effective gene therapy for this group of rare diseases.

The currently available information was reviewed in a series of presentations by the participating scientists. These presentations highlighted the status of the development of gene therapy for each of the diseases, as well as the problems and advantages presented by the different diseases.

Disabling mutations of both chains of the IFNg Receptor were described by Dr. Holland. His group has produced IFNgR1 and IFNgR2 expressing retroviral vectors and obtained productive transduction of B lymphocytes from an IFNgR1 deficient patient with the IFNgR1 retrovirus.

Leukocyte adhesion deficiency (LAD) is due to defects in the gene for the CD18 subunit of leukocyte adhesion molecules called integrins. Dr. Hickstein and his colleagues have achieved a 20% rate of transduction with a retroviral vector containing CD18 into CD34+ peripheral blood stem cells from a patient with LAD. Moreover, the treated cells showed functional correction. LAD is a particularly good candidate for gene therapy because less than normal levels of expression are required for significant correction of the clinical manifestations of the disease.

Chediak-Higashi syndrome (CHS) is an inherited disorder caused by mutations in the LYST gene. Dr. Brandt noted that there is mouse strain with the same genetic defect which will facilitate research. However, gene therapy for this disease presents difficulties because the gene is very large, and because correction is needed in nerve cells in addition to immune and hematopoietic cells.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder with variable clinical phenotypes which is caused by mutations of the WAS protein gene. Dr. Ochs and his colleagues are developing vectors containing the normal version of this gene for gene therapy. Non-random X inactivation in carrier females indicates that cells having a normal WAS protein gene have a survival advantage over those expressing the mutated form of the gene, suggesting that WAS is an excellent candidate disease for gene therapy.

Chronic granulomatous disease (CGD) is a genetic disease in which CGD phagocytes fail to produce the pathogen killing molecules superoxide and hydrogen peroxide due to mutations in the genes for the oxidase components. Dr. Malech described his development of gene therapy for this disease. In a phase I trial in the p47phox form of CGD, very small numbers of functional phagocytes were detected in the patients' blood for 3-6 months. He has now achieved high levels of gene transfer efficiency (50-80%) into CD34+ hematopoietic progenitor cells from patients with gp91phox CGD and will soon be using such corrected cells in an extension of the clinical trial. CGD is a particularly good candidate for gene therapy because low levels of functional phagocytes are expected to provide significant activity against pathogenic microbes.

The participants agreed that several of the inherited phagocyte disorders represented good candidates for gene therapy. Moreover, they felt that the problems involved in achieving highly efficient transduction into hematopoietic stem cells were likely to be solved because this was a focus of considerable research effort. However, a number of research areas were identified that would significantly contribute to the development of successful gene therapy for the inherited phagocyte disorders. They recommended the following areas for study:

Studies of Phagocyte Disorders Treated with Bone Marrow Transplantation/Registries

It was agreed that in certain of these disorders (e.g. LAD and CGD) the clinical manifestations of the disease could probably be prevented by less than 100% correction. However, the level of correction required is not known. Moreover, the long term outcome of introducing cells with normal expression of a gene product that is absent in the deficient individual is also not known (e.g. does the individual make an immune response against the newly introduced protein?). Information relevant to these questions could be obtained by long term follow-up studies on individuals with inherited phagocyte disorders who are treated with bone marrow transplantation. Registries would be one approach to obtaining this information.

Enhancement of Engraftment of Corrected Cells

It was considered likely that a conditioning regimen would be required both to enhance engraftment of corrected cells, and to prevent immune responses against the molecules produced by the newly introduced normal genes. Studies are required to identify the agents and regimens which would be efficacious while minimizing adverse effects.

Determine the Utility of Correction of Lineage Committed Cells

In certain cases permanent correction of the genetic defect by gene therapy may not be possible. An alternative approach is to utilize corrected, lineage committed, but long lived cells (e.g. alveolar macrophages) as an intervention. Studies to explore this approach were recommended.

Animal Models

The development of animal models of these disorders, particularly large animal models, would greatly facilitate research in correction of the inherited phagocyte diseases.



Howard B. Dickler, M.D.
Chief, Clinical Immunology Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A-19, National Institutes of Health
Bethesda, MD 20892-7640
Tel: 301-496-7104, Fax: 301-402-2571, E-mail:

Harry L. Malech, M.D.
Deputy Chief, LHD, National Institute of Allergy and Infectious Diseases, NIH
Bethesda, MD 20892-1886
Tel: 301-480-6916; Fax: 301-402-0789; E-mail:


Stephen J. Brandt, M.D.
Vanderbilt University Medical Center
Room 547, MRBII
Nashville, TN 37232
Tel: 615-936-1809; Fax: 615-936-1812; E-mail:

Mary-Ellen Conley, M.D.
St. Jude Children’s Research Hospital
Department of Immunology
570 St. Jude Place
Memphis, TN 38105
Tel: 901-495-2576; Fax: 901-495-3107; E-mail:

Dennis D. Hickstein, M.D.
Associate Professor of Medicine
VA Puget Sound Health Care System
1660 S. Columbia Way
Seattle, WA 98108
Tel: 206-764-2705; Fax: 206-764-2827; E-mail:

Steven M. Holland, M.D.
Senior Investigator, National Institute of Allergy and Infectious Diseases, NIH
Bethesda, MD 20892-1886
Tel: 301-496-7684; Fax: 301-402-4369; E-mail:

Harry L. Malech , M.D.
Deputy Chief, LHD, National Institute of Allergy and Infectious Diseases, NIH
Bethesda, MD 20892-1886
Tel: 301-480-6916; Fax: 301-402-0789; Email:

Hans D. Ochs, M.D.
Professor, Department of Pediatrics
University of Washington
School of Medicine Box 356320
Seattle, WA 98195-6320
Tel: 206-543-3207; Fax: 206-543-3184; E-mail:


Mary Dinauer, M.D., Ph.D.
Professor of Pediatrics and Medical and Molecular Genetics
Riley Hospital for Children, Cancer Research Institute, Room 466
1044 West Walnut
Indianapolis, IN 46202-5225
Tel: 317-274-8645; Fax: 317-274-8679; E-mail:

Jennifer M. Puck, M.D.
Deputy Director, Laboratory of Gene Transfer
National Center for Human Genome Research
Building 49, Room 3W14
National Institutes of Health
Bethesda, MD 20892-4470
Tel: 301-402-2194; Fax: 301-402-4929; E-mail:

C. I. Edvard Smith, M.D., Ph.D.
Associate Professor
Center for BioTechnology
Department of Biosciences at Novum
Karolinska Institute
S-14157 Huddinge, Sweden
Tel: 46-8-608-9114, Fax: 46-8-774-5538, E-mail:

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Last Updated August 08, 2005