OBJECTIVE: To examine the relationship between GGN and CAG trinucleotide repeat polymorphisms in the androgen receptor (AR) gene and indices of obesity in older Caucasian adults. DESIGN: A cross-sectional study. SUBJECTS: Ninety-nine healthy men (age 51 -93 y) and 113 healthy postmenopausal women (age 51 -92 y). MEASUREMENTS: Genotyping the GGN and CAG repeats of the AR gene, and measuring body weight, height and waist and hip circumferences. Waist was measured at the umbilicus (wstumb), iliac crest (wstili), and mid-way between the iliac crest and lowest rib (wstwst). Waist-to-hip ratios (WHRUMB, WHRILI and WHRWST) and body mass index (BMI) were calculated. RESULTS: Women who were homozygous for a common GGN (17 or 18) and short CAG ( 25) had higher waist and hip circumferences and higher WHRUMB and WHRWST, compared with women without this allele combination. The odds ratios (OR) for the upper 25th percentile of obesity measures were 3.6 -5.6-fold higher for wstumb, wstwst, WHRUMB and WHRWST among women with this allele combination. Men who had both a rare GGN (not 17) and short CAG ( 23) had a higher WHRUMB and WHRILI compared with men without this allele combination. The OR related to the upper 10th percentile of obesity measures among men who had this allele combination was 4.7-fold higher for WHRILI. CONCLUSION: AR GGN and CAG allele combinations are strongly associated with central obesity indices in older adults, particularly in women.
Duchenne muscular dystrophy (DMD) is a devastating primary muscle disease with pathological changes in skeletal muscle that are ongoing at birth. Progressive deterioration in striated muscle function in affected individuals ultimately results in early death due to cardio-pulmonary failure. Since affected individuals can be identified prior to birth by prenatal genetic testing for DMD, gene replacement treatment could be started in utero. This approach offers the possibility of preventing pathological changes in muscle that begin early in life. To test in utero gene transfer utilizing the AAV8 vector in the mdx mouse model of DMD, a minidystrophin gene driven by the human cytomegalovirus promoter was delivered systemically by intraperitoneal injection to the fetus at embryonic day 16. Treated mdx mice studied at 9 weeks after birth demonstrated widespread expression of recombinant dystrophin in skeletal muscle, restoration of the dystrophin associated glycoprotein complex in dystrophin-expressing muscle fibers, improved muscle pathology, and functional benefit to the transduced diaphragm compared to untreated littermate controls. These results support the potential of the AAV8 vector to efficiently cross the blood vessel barrier to achieve systemic gene transfer to skeletal muscle in utero in a mouse model of muscular dystrophy, to significantly improve the dystrophic phenotype and to ameliorate the processes that lead to exhaustion of skeletal muscle regenerative capacity.
Gene correction is attractive for single gene mutation disorders, such as Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD is dystrophin deficient due to a premature chain-terminating point mutation in exon 23 of the dystrophin gene. Gene editing of genomic DNA using single-stranded oligodeoxynucleotides (ssODNs) offers the potential to change the DNA sequence to alter mRNA and protein expression in defined ways. When applied to fetal skeletal muscle of mdx mice in utero, this technology leads to restoration of dystrophin protein expression, thus providing a valid gene-based therapeutic application at the earliest developmental stage. Here, we describe detailed methods for gene editing using muscle delivery of ssODNs to the fetal mdx mouse in utero at embryonic day 16 and to test correction of dystrophin deficiency at different ages after birth.
Adenoviral (Ad) vectors feature attractive characteristics for gene therapy of a wide variety of diseases. In many cases, the Ad vector must be administered using catheters and other plastic medical devices. Although poly(vinyl chloride) is one of the most frequently used catheter materials, it is relatively rigid and requires the addition of a plasticizer such as di-2-ethylhexyl phthalate (DEHP) to increase its flexibility. In this study, we demonstrated that exposure to a DEHP-containing catheter decreased the infectivity of Ad vectors but not the total particle number of the vector. Loss of Ad vector infectivity was directly related to the time of exposure to the DEHP-containing catheter, but it was not due to simple leaching of the chemical from the plastic. The loss of Ad vector infectivity could be prevented by preflushing the tube with albumin. Careful consideration of the compatibility between gene therapy vectors and medical delivery devices will be critical to the success of human gene therapy applications.
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