Genetic Rescue of Dystrophic Muscle In Utero

描述（由申请人提供）：尽管有许多基因转移到出生后骨骼肌有限区域的成功例子，但已证明难以进行适合于治疗遗传性肌肉疾病如杜氏肌营养不良症（DMD）的区域或全身递送。在胎儿阶段的基因或细胞转移具有更有效和更广泛的遗传互补DMD中的肌营养不良蛋白缺陷的潜力。对营养不良胎儿采取治疗策略的一个重要理由是，肌肉干细胞在胎儿肌肉中比在成人肌肉中更丰富。此外，病毒载体介导的基因传递和基因工程肌肉前体细胞移植到骨骼肌中可能在此胎儿阶段得到增强。因此，我们将探索在子宫内进行基因和细胞转移到肌肉的可行性，利用胎儿较低的组织质量和免疫不成熟以及肌肉发育的早期阶段的好处。 具体目标： 1.目的：评价高容量腺病毒（HC-Ad）载体在子宫内的抗肌萎缩蛋白基因传递。 2.评估使用腺相关病毒（AAV）载体的子宫内肌营养不良蛋白基因递送。 3.评估使用早期肌源性祖细胞的子宫内基因递送

DESCRIPTION (provided by applicant): Despite many successful examples of gene transfer to limited areas of postnatal skeletal muscle, regional or systemic delivery suitable to treat inherited muscle diseases such as Duchenne muscular dystrophy (DMD) has proved elusive. Gene or cell transfer during the fetal stage holds the potential of more efficient and widespread genetic complementation of dystrophin deficiency in DMD. An important rationale to pursue therapeutic strategies for the dystrophic fetus is that muscle stem cells are more plentiful in fetal muscle than in adult muscle. Furthermore, viral vector-mediated gene delivery and engraftment of genetically engineered muscle precursor cells to skeletal muscle may be enhanced during this fetal stage. Therefore, we will explore the feasibility of performing gene and cell transfer to muscle in utero exploiting the benefits of lower tissue mass and immune immaturity of the fetus as well as the earlier stage of muscle development. Specific Aims: 1. To evaluate in utero dystrophin gene delivery using high-capacity adenoviral (HC-Ad) vectors. 2. To evaluate in utero dystrophin gene delivery using adeno-associated viral (AAV) vectors. 3. To evaluate in utero gene delivery using early progenitor myogenic cells