Short-term growth hormone treatment in children with Hurler syndrome after hematopoietic cell transplantation.

Children with Hurler syndrome experience progressive growth failure after hematopoietic cell transplantation (HCT). The goal of this study was to review the safety and efficacy of growth hormone (GH) in eight children with Hurler syndrome who were treated at our institution with GH for short stature or GH deficiency between 2005 and 2008. The age at initiation of treatment with GH was 9.6+/-2.3 years and time since HCT was 7.5+/-1.5 years. Mean GH dose was 0.32 mg/kg/week. Baseline growth velocity was 3.5+/-1.5 cm/year (-2.6+/-1.9 s.d.), and it increased to 5.2+/-3.0 cm/year (-0.1+/-3.6 s.d.) after 1 year of treatment. Of the six patients with radiographic data, there was one progression of scoliosis, one progression of kyphosis and one progression of genu valgum. No patient discontinued treatment due to progression of skeletal disease. One patient discontinued GH due to slipped capital femoral epiphysis. Preliminary data suggest that 1-year GH treatment may modestly improve growth velocity in children with Hurler syndrome.

Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation.

Short stature is characteristic of Hurler syndrome, or mucopolysaccharidosis type IH (MPS IH). Hematopoietic stem cell transplantation (HSCT) is used to treat children with MPS IH. While HSCT corrects some of the metabolic features of MPS IH, its effects on growth are not well delineated. We investigated growth in patients with MPS IH after HSCT and described accompanying endocrine abnormalities. A cohort of 48 patients with MPS IH who had received HSCT between 1983 and 2005 were included. The prevalence of short stature (height <-2 s.d. score, SDS) before HSCT was 9%, and increased to 71% at last follow-up (6.9+/-5.1 years after HSCT). Short stature was positively associated with increased age at HSCT (P=0.002) and TBI (P=0.009). In total, 23% had growth hormone deficiency and/or low insulin-like growth factor-1, one female patient had premature adrenarche, one precocious puberty and 27% had clinical or subclinical hypothyroidism. Growth failure is highly prevalent in children with MPS IH after HSCT. Children who had no TBI exposure and were younger at the time of HSCT had a better height outcome.

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium.

A phase I clinical trial was conducted in which recombinant adenovirus containing the cystic fibrosis trans-membrane regulator (CFTR) (Ad2/CFTR) was administered by bronchoscopic instillation or aerosolization to the lungs of cystic fibrosis (CF) patients. In this paper, we evaluate the efficiency of Ad2/CFTR-mediated transduction of bronchial airway cells. The ability of an Ad2/CFTR vector to transduce airway cells was first evaluated in patients to whom the vector was administered by bronchoscopic instillation. Cells at the administration site were collected 2 days after treatment by bronchoscopic brushing. Ad2-specific CFTR DNA was detected in four of five individuals by PCR, and Ad2-specific CFTR RNA was detected in three of five individuals by RT-PCR. Ad2/CFTR-mediated transduction of airway epithelial cells was then determined in CF individuals receiving this vector by aerosol inhalation. Ad2-specific CFTR DNA was detected in 13 of 13 individuals 2 days after aerosolization, and in 3 of 5 individuals 7 days after aerosolization. Ad2-specific RNA was detected in 4 of 13 individuals on day 2, but was not detected in the 5 individuals tested on day 7. The percentage of airway epithelial cells containing nuclear-localized vector DNA was < or =2.4% as determined by fluorescence in situ hybridization (FISH). However, in some cases, a high percentage of nonepithelial mononuclear cells or squamous metaplastic epithelial cells was infected with the adenoviral vector. In conclusion, aerosol administration is a feasible means to distribute adenoviral vectors throughout the conducting airways, but improvements in adenovirus-mediated transduction of airway epithelial cells are necessary before gene therapy for CF will be effective.

Adenoviral vector expressing ICP47 inhibits adenovirus-specific cytotoxic T lymphocytes in nonhuman primates.

Studies from several laboratories have shown that administration of E1-deleted Ad vectors results only in transient transgene expression in the lungs of immunocompetent animals. This is due, at least in part, to destruction of vector-transduced cells by host cellular immune responses (predominantly CD8(+) CTLs) directed against viral proteins and/or immunogenic transgene products. We have previously demonstrated that E1-deleted Ad vectors can lead to persistent expression of human cystic fibrosis transmembrane conductance regulator (hCFTR) in the lungs of several strains of immunocompetent mice, despite the presence of Ad-specific CTLs. However, we found that these same vectors gave rise only to transient hCFTR expression in the lungs of rhesus monkeys. We have constructed new Ad vectors that coexpress both hCFTR and the ICP47 gene from herpes simplex virus. ICP47 has been shown to inhibit the transporter associated with antigen presentation, thus blocking major histocompatibility antigen I (MHC class I)-mediated antigen presentation to CD8(+) T cells. The Ad/hCFTR/ICP47 vector decreased levels of cell-surface MHC class I molecules on infected monkey and human cell lines. Similar results were obtained with primary human cells and primary monkey airway epithelial cells. In vitro studies showed that the Ad/hCFTR/ICP47 vector decreased cytolysis by both monkey and human CTLs. When Ad/hCFTR/ICP47 was administered to the lungs of rhesus monkeys, it inhibited the generation of Ad-specific CTLs. However, natural killer cell activity was enhanced in monkeys treated with the Ad/hCFTR/ICP47 vector.