Genetic Rescue of Dystrophic Mucle In Utero

描述(申请人提供)：尽管有许多成功的例子将基因转移到出生后骨骼肌的有限区域，但事实证明，适合于治疗遗传性肌肉疾病(如Duchenne肌营养不良症(DMD))的区域性或全身性转移是难以实现的。在胎儿阶段进行基因或细胞转移，有可能对DMD中的Dstrophin缺乏症进行更有效和更广泛的遗传互补。寻求营养不良胎儿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植入骨骼肌可能在这个胎儿阶段得到加强。因此，我们将探索将基因和细胞转移到子宫内肌肉的可行性，利用胎儿较低的组织质量和免疫未成熟以及肌肉发育的早期阶段的好处。 具体目标： 1.评价大容量腺病毒载体(HC-Ad)在宫内转导dystrophin基因的效果。 2.对腺相关病毒(AAV)载体在宫内转导dystrophin基因的效果进行评价。 3.评价早期祖细胞肌源性细胞在子宫内的基因传递

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