A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

Reproductive health in males with cystic fibrosis: knowledge, attitudes, and experiences of patients and parents.

Males with cystic fibrosis (CF) are generally infertile as a result of aberrant development of Wolffian duct derivitives. The personal significance of this and related reproductive and sexual health (RSH) issues is unknown. We set out to describe the knowledge, attitudes, and experiences regarding RSH in a group of adolescent and adult males with CF, as well as the knowledge and attitudes of parents. This descriptive study was based on a semi-structured interview utilizing in-depth interview techniques. Questions included aspects of knowledge, attitudes, and experiences. Adolescent (aged 14-17 years) and adult (at least 18 years) males attending the Children's Hospital Cystic Fibrosis Clinic, Boston, MA, USA, or hospitalized at the Children's Hospital over that period were eligible; the accompanying parent of the adolescent was also interviewed. Consecutive eligible males were interviewed over a 3 month period. Summary data are presented, attitudinal data are analyzed qualitatively, and a selection of representative transcript data are reported to describe the range of opinions. Fifty males (10 adolescents, 40 adults) participated; this constituted a consecutive sample of 44% of the eligible clinic population. Ninety percent of adults, 60% of adolescents, and 50% of parents knew of male infertility. The mean age (+/-SD) at which adults recalled first hearing this was 16.0 +/- 4.7 years and 13.9 +/- 1.6 years for those adolescents who knew of infertility. Nineteen (48%) of adults and 5 (83%) of adolescents first heard about infertility from their health care providers. Ninety percent reported no major distress upon first hearing about infertility during adolescence. Increasing significance of infertility with maturity was reported by 12 men (30%); only 4 adults (10%) reported that infertility was not a significant aspect of CF. Forty percent knew that males with CF have a small volume ejaculate, but none had been told this by a health care provider. Thirty percent of men had semen analysis performed and all were azoospermic. We conclude that the majority of males with CF know of likely infertility. The significance of this knowledge changes with time. Poor knowledge and confusion surround a range of RSH issues in males with CF.

PIP: Reproductive and sexual health issues are often neglected in work with patients with chronic, life-limiting diseases. Aberrant development of Wolffian duct derivatives generally leads to infertility in men with cystic fibrosis. The reproductive health-related knowledge, attitudes, and experiences of adolescent and adult males with cystic fibrosis were investigated in a descriptive study conducted at the Children's Hospital Cystic Fibrosis Clinic in Boston, Massachusetts (US). Enrolled were 10 adolescents 14-17 years old (mean age, 16 years) and 40 adult men 18-53 years old (mean age, 29 years). 90% of adults, 60% of adolescents, and 50% of parents of adolescent patients were aware of the risk of infertility associated with cystic fibrosis. The average age at which the adult men first learned of this risk was 16 years. A health care provider was the source of this knowledge for 48% of adults and 83% of adolescents. 90% of adult men reported no major distress upon first hearing of the likelihood of infertility during adolescence; however, the emotional significance of possible infertility increased over time for 30%. 20% confused infertility with impotence. 30% of adult men had requested semen analyses and all were azoospermic. There was agreement among respondents that 14 years of age is an appropriate time for health care providers to initiate discussions about the impact of cystic fibrosis on reproductive health. Semen analysis is important to offer all men with cystic fibrosis, providing it is coupled with counseling if azoospermia is confirmed.