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Gene transfer into haematopoietic stem cells ( HSCs) has now come to the stage where it can be recognized as a form of established therapy for patients with a certain range of genetic diseases. Primary immunodeficiency disease ( PID) represents an ideal pathological target for this type of genetic medicine, that is HSC gene therapy, as exemplified well by the successful cases with adenosine-deaminase ( ADA) deficiency. Other diseases including X-linked severe combined immunodeficiency disease ( X- SCID), chronic granulomatous disease ( CGD) and Wiskott- Aldrich syndrome ( WAS) have also been the targets of gene therapy, but the efficacy reportedly varies considerably. In addition, all those diseases except ADA deficiency have been demonstrated to be subject to an inherent risk of insertional leukaemogenesis as long as gene transfer accompanies genomic insertion. Researchers therefore should continue to aim for further improvement of HSC gene therapy to maximize both safety and efficacy. To achieve this aim, an ideal model system is desired, by which faithful recapitulation of the disease-related pathophysiology is feasible. Recently, a new model system possibly constituting such an ideal platform has come to reality; that is, patient-/disease-specific induced pluripotent stem cells ( iPSCs). iPSCs should particularly be useful for modelling genetic disorders, because of their excellent potential to differentiate into any types of somatic cells while retaining the patient-specific genetic mutations. These model cells should allow testing various kinds of genetic manipulation and also detailed analysis of the target cells before/after differentiation, thus providing a disease-specific platform for preclinical studies to test safety and efficacy of each gene-modification procedure. [ABSTRACT FROM AUTHOR]

Fujioka H, Ariga T, Horiuchi K, Otsu M, Igawa H, Kawashima K, Yamamoto Y, Sugihara T, Sakiyama Y. Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I.HumanGLI3gene mutations have been identified in several phenotypes of digital abnormality such as Greig cephalopolysyndactyly syndrome, Pallister–Hall syndrome, preaxial polydactyly type-IV (PPD-IV) and postaxial polydactyly. However, the different phenotypes resulting fromGLI3mutations have not yet been properly defined. We have experienced two types of digital abnormality without other complicating developmental defects; a family with foot PPD-IV with syndactyly of the third and fourth fingers, and four sporadic cases with biphalangeal thumb polydactyly (PPD-I). The genes responsible for syndactyly of the third and fourth fingers (syndactyly type-I) and PPD-I have not yet been identified; we therefore examined the involvement of theGLI3gene in these subtypes of digital abnormality. We found a non-sense mutation in theGLI3gene in the family with foot PPD-IV accompanied with hand syndactyly of the third and fourth fingers, but no mutations were detected in theGLI3gene in the four other cases with PPD-I alone. Thus, the phenotype of foot PPD-IV accompanied with hand syndactyly of the third and fourth fingers may result from aGLI3mutation, whereas the PPD-I phenotype alone is not caused byGLI3gene defect. These results will help to define the phenotypic spectrum ofGLI3morphopathies, which have been recently proposed. [ABSTRACT FROM AUTHOR]

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher ( P <0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality ( P <0.001 by log-rank test), the incidence of fatal aortic rupture ( P =0.08), and aortic dissection ( P <0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.