NFP37 SOMATIC GENE THERAPY Texts for Laypersons

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Dr. Jovan Mirkovitch;	ISREC; Chemin des Boveresses 155; 1066 Epalinges; CH; Tel 021 692 59 20; Fax 021 652 69 33 e-mail: jovan.mirkovitch@isrec.unil.ch
Title:	Faithful regulation of the btk gene for XLA therapy.
Co-applicants:
Collaborators:
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ABSTRACT FOR LAYPERSONS 1997:

XLA, the first immunodeficiency described about 40 years ago, results from the inability of precursor cells to develop into mature B cells, the cells that produce antibodies. Patients with that disease can not develop a normal antibody response. Defects in the recently cloned Btk gene are the major cause of XLA. In order to correct these defects, the Btk function should be brought back into precursor B cells. As Btk is expressed only in cells from hematopoietic origin, XLA seems to be an ideal defect to correct by gene therapy of bone marrow precursor cells.

However, as Btk encodes a tyrosine kinase, a type of protein which is involved in cell proliferation and differentiation, gene therapy should be attempted when stringent control of Btk expression can be achieved. Our results should help clinician collaborators to devise vectors expressing Btk at appropriate levels in a tissue-specific manner, such as to perform hematopoietic stem cell gene therapy of XLA.

The first phase of gene expression called transcription, where the DNA sequence is transcribed into RNA molecules, is the critical step of Btk regulation. Our goal is to identify the elements which are responsible for the precise regulation of Btk transcription in normal B cell. After these elements are identified, we plan to use them to achieve a precisely controled expression of Btk. Identification and the use of the authentic regulators of Btk transcription should allow us to obtain a very precise expression of Btk when it is reintroduced back in its natural cell environment.

Our laboratory has specialise-d into applying state of the art approaches for the identification of such regulatory elements. These consist mostly in analysing the structures formed in intact cells by the DNA and its associated proteins. Although these approaches are difficult to perform, their results are very significant, and may identify elements which could not be found by easier approaches.

XLA, the first immunodeficiency described about 40 years ago, results from the inability of precursor cells to develop into mature B cells, the cells that produce antibodies. Patients with that disease can not develop a normal antibody response. Defects in the recently cloned Btk gene are the major cause of XLA. In order to correct these defects, the Btk function should be brought back into precursor B cells. As Btk is expressed only in cells from hematopoietic origin, XLA seems to be an ideal defect to correct by gene therapy of bone marrow precursor cells.However, as Btk encodes a tyrosine kinase, a type of protein which is involved in cell proliferation and differentiation, gene therapy should be attempted when stringent control of Btk expression can be achieved. Our results should help clinician collaborators to devise vectors expressing Btk at appropriate levels in a tissue-specific manner, such as to perform hematopoietic stem cell gene therapy of XLA.The first phase of gene expression called transcription, where the DNA sequence is transcribed into RNA molecules, is the critical step of Btk regulation. Our goal is to identify the elements which are responsible for the precise regulation of Btk transcription in normal B cell. After these elements are identified, we plan to use them to achieve a precisely controlled expression of Btk. Identification and the use of the authentic regulators of Btk transcription should allow us to obtain a very precise expression of Btk when it is reintroduced back in its natural cell environment.Our laboratory has specialised into applying state of the art approaches for the identification of such regulatory elements. These consist mostly in analysing the structures formed in intact cells by the DNA and its associated proteins. Although these approaches are difficult to perform, their results are very significant, and may identify elements which could not be found by easier approaches.

text (font Courier, corps 3)

text (font Courier, corps 3)

text (font Courier, corps 3)

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