AAV Gene Therapy: A Potential Breakthrough for Rare Disease Treatment

Seven-year-old Canadian child Michael Piravola was diagnosed with a mutation in his AP4M1 gene at just 18 months old. By the age of two, he was diagnosed with hereditary spastic paraplegia type 50, an ultra-rare condition characterized by developmental delays, microcephaly, speech impairments, and limitations in standing and walking.

Recently, research teams from institutions such as the Children’s Hospital in Canada and Boston Children’s Hospital employed adeno-associated virus (AAV) therapy, using AAV serotype 9 (AAV9) as a vector. Through intrathecal injection, they introduced a normal AP4M1 gene into Michael’s body. After a period of treatment, Michael showed significant improvement; he can now stand on his heels for extended periods and walk with the aid of assistive devices. Michael is not the first patient to benefit from AAV gene therapy. Over decades of development, AAV gene therapy has made breakthroughs in treating various conditions, including tumors, blood disorders, retinal diseases, and hereditary deafness, offering to hope to many patients.
The gene therapy involves delivering therapeutic exogenous genes into target cells in the human body, aiming to correct genetic defects or abnormalities. This approach transcends the limitations of traditional medications, enabling precise treatment for a variety of diseases and holding the potential for fundamentally curing conditions.

The gene therapy vectors are generally classified into viral and non-viral types, with viral vectors offering advantages such as a broad host range and prolonged effects. Consequently, the gene therapy often employs viral vectors as delivery systems. In addition to AAV, commonly used viral vectors include adenoviruses (AdV), retroviruses (RV), and lentiviruses (LV).
AAV has three notable characteristics. First, it is highly safe. Data indicates that over half of the population has been infected with AAV without developing any illness. Currently, scientists use recombinant AAV (rAAV) in clinical applications. This virus has had 96% of its wild-type AAV genes removed, is non-replicative, and possesses low rates of genomic integration and immunogenicity, further ensuring safety. Second, rAAV provides lasting expression. It can maintain long-term expression of exogenous genes in target cells, which is particularly crucial for genetic diseases requiring sustained therapeutic effects. Finally, it has a broad host range, capable of infecting various mammalian cells, including both dividing and non-dividing cells.
Given these attributes, AAV vectors are considered the most promising gene therapy delivery systems currently available, offering unique advantages in treating various genetic and rare diseases. Data shows that over 70% of gene delivery drugs utilize AAV for their delivery. Driven by vast market potential and significant patient demand, numerous pharmaceutical companies and research teams are actively advancing their studies. As of now, eight AAV gene therapy products have been approved for marketing use globally. The most commonly used AAV vectors in clinical applications include AAV1, AAV2, AAV5, AAV8, and AAV9, which have been successfully applied in gene therapies for conditions such as congenital blindness, hemophilia, and spinal muscular atrophy across ophthalmology, hematology, and neurology.

Despite the promise of AAV gene therapy, its transition to clinical application faces multiple challenges. Experts indicate that current gene therapies primarily target single-gene hereditary diseases, while therapies for polygenic hereditary diseases and acquired conditions are still under development. Additionally, the safety and efficacy of gene therapies require further observation.