In utero delivery of oligodeoxynucleotides for gene correction.

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.

Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a minidystrophin gene.

Duchenne muscular dystrophy (DMD) is a devastating primary muscle disease with pathological changes in skeletal muscle that are ongoing at the time of birth. Progressive deterioration in striated muscle function in affected individuals ultimately results in early death due to cardio-pulmonary failure. As affected individuals can be identified before birth by prenatal genetic testing for DMD, gene replacement treatment can be started in utero.

Systemic delivery of AAV8 in utero results in gene expression in diaphragm and limb muscle: treatment implications for muscle disorders.

One of the major challenges in the treatment of primary muscle disorders, which often affect many muscle groups, is achieving efficient, widespread transgene expression in muscle. In utero gene transfer can potentially address this problem by accomplishing the gene delivery when the tissue mass is small and the immune system is immature. Earlier studies with systemic in utero adeno-associated viral (AAV) vector serotype 1 gene delivery to embryonic day 16 (E-16) pups resulted in high levels of transduction in diaphragm and intercostal muscles, but no detectable transgene expression in limb muscles.

Full-length dystrophin gene transfer to the mdx mouse in utero.

In utero gene therapy for genetic diseases, such as muscular dystrophies, offers potential advantages over postnatal treatment including vector delivery at the earliest point in the disease and treatment prior to full maturation of the immune system. This study examines in utero gene delivery of full-length murine dystrophin to the murine mdx model for Duchenne muscular dystrophy using a high-capacity adenoviral vector. We examined dystrophin expression, spread of vector, morphology and specific force production of the tibialis anterior muscle 9 weeks after intramuscular in utero injection.

Biocompatibility of adenoviral vectors in poly(vinyl chloride) tubing catheters with presence or absence of plasticizer di-2-ethylhexyl phthalate.

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.