Xiao Xiao

Xiao Xiao, Ph.D., is the Fred Eshelman Distinguished Professor of Gene Therapy and Director of Gene Therapy Research at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy. He is also co-founder of Asklepios BioPharmaceutical Inc. (AskBio), established in 2003 with R. Jude Samulski. Dr. Xiao is internationally recognized as a pioneer in AAV-mediated gene therapy for Duchenne muscular dystrophy (DMD). The dystrophin gene—one of the largest human genes at 2.4 Mb DNA encoding a 14 kb mRNA—far exceeds the ~4.7 kb packaging capacity of AAV vectors. In 2000, Xiao's laboratory first engineered a miniaturized yet functional "micro-dystrophin" gene (~3.5-4 kb) by rationally designing a construct retaining critical functional domains (N-terminus, C-terminus, selected spectrin-like repeats) while eliminating non-essential regions. This groundbreaking micro-gene effectively ameliorated the dystrophic phenotype in mdx mice, establishing the foundation for AAV-based DMD gene therapy. Xiao's micro-dystrophin design is recognized as one of the first protective micro-gene constructs (alongside Chamberlain lab's 2002 work). AskBio acquired intellectual property rights to Xiao's uniquely miniaturized dystrophin gene, which has been licensed by companies including Pfizer and Solid Biosciences for clinical trial development. Beyond micro-dystrophin engineering, Xiao's laboratory made pioneering contributions to systemic AAV delivery. In 2005, his team demonstrated that AAV serotype 8 (AAV8) efficiently transduces whole-body skeletal and cardiac muscle following peripheral injection without pharmacological intervention—a breakthrough enabling minimally invasive systemic gene transfer. In 2010, Xiao's team validated widespread muscle expression of AAV9-delivered micro-dystrophin in neonatal GRMD dogs (a large animal DMD model) after single intravenous injection, providing critical proof-of-concept for clinical translation. Xiao served as principal investigator for the first DMD gene therapy clinical trial (2006-2010, Columbus Children's Hospital). While the trial uncovered immune response barriers, it provided crucial insights into patient immune reactions to dystrophin protein. As AskBio co-founder, Xiao successfully translated academic research into commercial impact; Bayer acquired AskBio for $4 billion in 2020, validating the commercial potential of AAV muscle gene therapies.

Xiao Xiao哲学博士，是北卡罗来纳大学教堂山分校埃舍尔曼药学院Fred Eshelman杰出基因治疗教授和基因治疗研究主任。他还是2003年与R. Jude Samulski共同创建的Asklepios BioPharmaceutical Inc. (AskBio)的联合创始人。 Xiao博士国际公认为杜氏肌营养不良症(DMD) AAV介导基因治疗的先驱。肌营养不良蛋白基因——人类最大的基因之一，2.4 Mb DNA编码14 kb mRNA——远超AAV载体约4.7 kb的包装容量。2000年，Xiao实验室首次通过理性设计构建保留关键功能域（N端、C端、选定的spectrin样重复序列）同时消除非必需区域，工程化了缩小但仍具功能的"微肌营养不良蛋白"基因（约3.5-4 kb）。这个开创性的微基因在mdx小鼠中有效改善了肌营养不良表型，为基于AAV的DMD基因治疗奠定了基础。 Xiao的微肌营养不良蛋白设计被认为是首个具有保护性的微基因构建之一（与Chamberlain实验室2002年的工作并列）。AskBio获得了Xiao独特微肌营养不良蛋白基因的知识产权，该技术已被辉瑞和Solid Biosciences等公司授权用于临床试验开发。 除了微肌营养不良蛋白工程化，Xiao实验室在AAV系统性递送方面做出了开创性贡献。2005年，他的团队证明AAV血清型8 (AAV8)在外周注射后无需药物干预即可高效转导全身骨骼肌和心肌——这一突破实现了微创系统性基因转移。2010年，Xiao团队在新生GRMD犬（DMD大型动物模型）中验证了单次静脉注射后AAV9递送的微肌营养不良蛋白的广泛肌肉表达，为临床转化提供了关键概念验证。 Xiao担任首个DMD基因治疗临床试验（2006-2010，哥伦布儿童医院）的主要研究者。虽然试验揭示了免疫反应障碍，但它为理解患者对肌营养不良蛋白的免疫反应提供了关键见解。作为AskBio联合创始人，Xiao成功地将学术研究转化为商业影响；Bayer于2020年以40亿美元收购AskBio，验证了AAV肌肉基因治疗的商业潜力。