Chinese scientists find new method for large cargo delivery in gene therapy

Delivery of therapeutic genes is essential for gene therapy. Adeno-associated viruses (AAVs) are a prime vector for carrying gene cargoes because of their superior gene segmentation flexibility and robust gene reconstitution efficiency. However, their limited packaging capacity is a major challenge for large gene transduction.

Professor Lu Zhonghua's team from the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences, and collaborators from Peking University First Hospital, developed the AAV with translocation LINKage (AAVLINK), which harnesses Cre/lox-mediated intermolecular DNA recombination to enable in vivo reassembly of large genes. 

The findings provided strong evidence that AAVLINK supported functional delivery of large therapeutic genes in the nervous system, which were published in the international academic journal Cell.

Currently, more than 7,000 rare diseases have been identified worldwide. Most of these conditions are caused by genetic mutations and lack of effective treatments, posing a significant challenge to human medicine. In recent years, gene therapy has emerged as a novel therapeutic technique, offering new hope for treating genetic diseases like rare disorders through methods such as repairing, replacing or suppressing disease-causing genes.

Utilizing AAVLINK strategy, the researchers constructed a vector bank covering 193 large genes associated with inherited disorders including autism and epilepsy. They validated the gene reconstitution capacity of all constructs. Also, this vector bank comprised five CRISPR-based genetic tools, offering insights into the wide application of AAVLINK.

The study proposes a strategy to facilitate the delivery of large gene cargoes by using AAVs, which provides therapeutic possibilities for diseases that have been considered inaccessible to AAV-based gene therapy.

(Cover: Professor Lu Zhonghua's team conducts a qPCR experiment. /Courtesy of Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences)