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Journal of Clinical Investigation

JCI online early table of contents: August 7, 2008

DERMATOLOGY: Possible new treatment for psoriasis

New data, generated by Thomas Jung and colleagues, at Novartis Exploratory Development, Switzerland, have indicated that a drug known currently as AEB071 can reduce the clinical symptoms of psoriasis, a chronic, currently incurable autoimmune skin disease.

In the study, healthy volunteers and patients with psoriasis were administered AEB071 by mouth. Different groups of individuals received different doses of the drug, but all doses were well tolerated with no obvious side effects. The decrease in the clinical symptoms of psoriasis was associated with a decreased ability of immune cells known as lymphocytes to divide and express a soluble factor known as IL-2. The authors therefore suggest that AEB071 might be an effective new treatment for psoriasis, although they caution that further clinical trials are needed to more clearly establish that the drug is safe and effective.

TITLE: The PKC inhibitor AEB071 may be a therapeutic option for psoriasis

AUTHOR CONTACT:

Thomas Jung
Novartis Exploratory Development, Basel, Switzerland.
Phone: 41-61-3247340; Fax: 41-61-3240810; E-mail: thomas.jung@novartis.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35636


GENE THERAPY: Why gene therapy caused leukemia in some "Boy in the bubble syndrome" patients

Severe combined immunodeficiency (SCID), sometimes called 'Boy in the bubble syndrome', is a genetic disorder in which the patient lacks most types of immune cell. Almost 10 years ago, two independent groups (one in London, United Kingdom, and one in Paris, France) used gene therapy to treat a few infants with the most common form of SCID, SCID-X1, which is caused by mutations in the IL2RG gene. Although most infants showed dramatic improvement following gene therapy, 4 of the 9 infants that were successfully treated in Paris developed leukemia between 3 and 6 years after the treatment. The groups in London and Paris had used very similar gene therapy approaches and until now it was not clear why leukemia was detected only in some of the infants treated in Paris. However, Adrian Thrasher and colleagues, at the Institute for Child Health, London, now report that 1 of the infants successfully treated in London also developed a form of leukemia known as T cell acute lymphoblastic leukemia (T-ALL).

In the study, Thrasher and colleagues go on to show why that infant developed leukemia. During gene therapy, the correct form of the IL2RG gene and the vector that carried this into the cells integrated into part of the genome that contained a gene known as LMO2 and activated this gene. In combination with other genetic mutations that were not caused by the gene therapy (including activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and translocation of the TCRb gene into the SIL-TAL1 locus), this caused the development of leukemia.

In a related paper by Salima Hacein-Bey-Abina and colleagues, the researchers in Paris who performed the other gene therapy trial have now identified similar reasons to explain why 2 of the 4 infants that developed leukemia became sick. In one patient, the gene and vector integrated into the part of the genome that contained LMO2 and activated the gene, and in the other patient, the gene and vector integrated into part of the genome that contained a gene known as CCND2 and activated this gene. In both infants, other genetic mutations not caused by the gene therapy contributed to the development of leukemia and these mutations were very similar to those observed in the patient treated in London (activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and rearrangement of the SIL-TAL1 locus).

The authors of both studies hope that these data provide insight that will help in the design of future gene therapy protocols to ensure similar efficacy but decreased toxicity.

TITLE: Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1

AUTHOR CONTACT:

Salima Hacein-Bey-Abina
Hôpital Necker–Enfants Malades, Paris, France.
Phone: 33-1-44-38-15-27; Fax: 33-1-42-73-06-40; E-mail: salima.hacein-bey@nck.ap-hop-paris.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35700

RELATED MANUSCRIPT

TITLE: Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients

AUTHOR CONTACT:

Adrian J. Thrasher
Institute for Child Health, London, United Kingdom.
Phone: 44-207-8138490; Fax: 44-207-9052810; E-mail: a.thrasher@ich.ucl.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35798


VASCULAR BIOLOGY: Softly, softly: drugs that block the protein KCa3.1 reduce hardening of mouse arteries

One of the most common causes of death in the developed world is a disease of the major arterial blood vessels that can cause heart attacks and stroke. Although treatments that lower cholesterol levels and blood pressure have proven successful at combating this disease, which is known as atherosclerosis (or hardening of the arteries), the continuing high incidence of atherosclerosis indicates that new therapeutic approaches are still needed. And now, Hiroto Miura and colleagues, at the Medical College of Wisconsin, Milwaukee, have identified a possible new therapeutic strategy through their analysis of humans and mice with atherosclerosis.

In the study, it was observed that arterial blood vessels from both humans with atherosclerosis and mice with atherosclerosis (specifically mice lacking the gene ApoE) expressed higher levels of a protein known as KCa3.1 than the same blood vessels from healthy humans and mice. Consistent with an important role for this protein in the development of atherosclerosis, when mice lacking ApoE were treated with either of two drugs that block KCa3.1 they were substantially protected from the disease. Further, several cells involved in atherosclerosis exhibited decreased in vitro function if they came from mice lacking KCa3.1 and the function of these same cells from humans was diminished in vitro by both drugs that block KCa3.1 and genetic knockdown of KCa3.1 expression. The authors therefore suggest that drugs that block KCa3.1 might help reduce the incidence of atherosclerosis.

TITLE: The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

AUTHOR CONTACT:

Hiroto Miura
Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Phone: (414) 456-5639; Fax: (414) 456-6572; E-mail: hmiura@mcw.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30836

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