Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.

PURPOSE: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. METHODS: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. RESULTS: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. CONCLUSIONS: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

Comparison of physical activity in adolescents with cystic fibrosis versus age-matched controls.

The aims of this study were to compare self-reported vigorous physical activity and participation in sports among adolescents with cystic fibrosis (CF) to those of age matched peers from the general population, and to determine which CF patient characteristics are associated with regular physical activity. One hundred and sixteen of 141 (82%) adolescents aged 12-19 years identified through North Carolina CF Care Center registries confidentially completed a self-administered questionnaire (the CDC's Youth Risk Behavior Survey) addressing health-compromising and health-enhancing behaviors, including physical activity. They were age- and gender-matched to adolescents from North Carolina schools who completed the same survey. Adolescents with CF did not differ significantly from their matched peers with regard to participating three or more times a week in activities that "make you sweat or breathe hard" (63% vs. 67%, P = 0.37), physical education class (59% vs. 61%, P = 0.81), or team sports (52% vs. 61%, P = 0.10). For all categories of activity, participation declined among adolescents aged 17 years or older. After adjusting for gender and health status, early (14 years or younger) and middle (15-16 years) adolescents were more likely to participate in all three types of activity than older adolescents with CF. Like their peers in the general population, adolescents aged 17 and older are much less likely to report regular physical activity, or participation in physical education class or in team sports. Healthcare providers should be aware of this decline in activity in late adolescence and should consider efforts to maintain physical activity among older teenagers and young adults.

Cystic fibrosis: combined hyperpolarized 3He-enhanced and conventional proton MR imaging in the lung--preliminary observations.

Four patients with cystic fibrosis (CF) were examined with combined hyperpolarized helium 3-enhanced and conventional proton magnetic resonance (MR) imaging. After inhalation of the polarized 3He gas, single breath-hold, gradient-echo images (resonant frequency of 3He) were obtained to depict lung ventilation. Conventional T2-weighted fast spin-echo (hydrogen) images were also obtained to depict morphologic abnormalities. 3He images were successfully and reproducibly generated that showed both morphologic abnormalities and, often more extensive, ventilation abnormalities. 3He MR imaging may provide a method for evaluating progression of pulmonary disease in patients with CF.

Preventive services received by adolescents with cystic fibrosis and sickle cell disease.

OBJECTIVE: To determine the proportion of adolescents with cystic fibrosis (CF) or sickle cell disease (SCD) who reported speaking with their physicians about health-promoting and risky behaviors and whether the rate of discussions varied by whether the main physician was a primary care provider or specialist. HYPOTHESIS: Adolescents reporting a primary care provider as their main physician would be more likely to have received risk behavior counseling and other preventive services. DESIGN: Survey. SETTING: Comprehensive CF and SCD centers in 5 North Carolina referral hospitals. PARTICIPANTS: Three hundred twenty-one (74%) of 437 adolescents aged 12 through 19 years (mean age, 15.6 years; 51% male) with CF or SCD identified through center registries. MAIN OUTCOME MEASURES: Sources of health care, main physician, and recall of discussions with physicians regarding sexual issues, substance use, weight or dieting, safety issues, depression, and violence. RESULTS: Adolescents with CF (53%) or SCD (46%) most commonly reported a specialist as their main physician. For those (83%) who saw their main physician in the past year, adolescents with SCD reported counseling rates ranging from 43% for sexuality to 15% for weapon carrying or fighting. For adolescents with CF, rates ranged from 65% for weight and dieting to 30% for sexuality and 6% for weapon carrying or fighting. Adolescents whose main physician was a primary care provider were no more or less likely to report counseling for any topic (all P>.05). CONCLUSIONS: Physicians, regardless of specialty, infrequently discussed common behavioral issues with these adolescents with CF or SCD. A coordinated effort between primary care physicians and specialists may be helpful in delivering optimal preventive services to this population.

Risky behavior in teens with cystic fibrosis or sickle cell disease: a multicenter study.

OBJECTIVE: To determine the prevalence and age of onset of common risky behaviors such as smoking and sexual activity in teens with cystic fibrosis and those with sickle cell disease and to compare their behaviors with those of adolescents in the general population. DESIGN: Survey. SETTING: All five major pediatric tertiary care centers in North Carolina (study participants with sickle cell disease or cystic fibrosis) and North Carolina public schools (comparison population). PARTICIPANTS: Three hundred twenty-one adolescents with cystic fibrosis or sickle cell disease aged 12 to 19 years (mean age, 15.6 years; 49% female). Demographically matched comparison teens for each group were selected from 2760 in-school adolescents (mean age, 16.0 years; 51% female). MAIN OUTCOMES MEASURES: Prevalence of tobacco and marijuana use, alcohol use, sexual intercourse, sexually transmitted diseases, seat belt use, weapon carrying, and age of onset of these behaviors. RESULTS: Chronically ill teens reported significantly less lifetime and current use of tobacco, marijuana, and alcohol; less sexual intercourse; less weapon carrying, less drunk driving, and more seat belt use than their peers. Nonetheless, 21% of the teens with cystic fibrosis and 30% of those with sickle cell disease had smoked; sexual intercourse was reported by 28% and 51%, respectively. Age of onset of these behaviors was frequently older for the chronically ill teens. CONCLUSION: Teens with cystic fibrosis or sickle cell disease took more potentially damaging health risks than might be expected, although the prevalence was lower than reported by their peers. Future longitudinal studies should examine the relationships between chronic illness, physical and psychosocial maturation, and risky behavior. Screening for psychosocial issues, including risky behaviors, should be incorporated into the routine health care of chronically ill teens.