Researchers Develop AAVLINK Breakthrough to Deliver Oversized Genes via AAV Vectors

January 28, 2026 – A major advance in AAV gene therapy may significantly expand the range of diseases addressable by AAV-based gene delivery. Researchers in China have developed a new AAV platform, termed AAVLINK, that overcomes the long-standing AAV packaging limit, enabling efficient delivery of large genes previously incompatible with AAV vectors.

Adeno-associated virus (AAV) remains the dominant viral vector in gene therapy due to its favorable safety profile, broad tissue tropism, and durable transgene expression. However, the intrinsic AAV genome size constraint (~4.7–5 kb) has excluded many disease-causing genes from AAV gene therapy development. Notably, more than one-third of autism-associated genes, along with key genes linked to epilepsy, muscular dystrophy, and neurodevelopmental disorders, exceed conventional AAV vector capacity.

The AAVLINK system addresses this limitation by splitting oversized genes into two or three fragments, packaging each fragment into separate AAV vectors, and enabling precise intracellular reassembly. This split-AAV gene therapy strategy uses Cre recombinase–mediated recombination to reconstruct full-length genes within target cells. Importantly, Cre expression is self-terminating after recombination, mitigating safety concerns that have historically limited recombinase-based AAV approaches.

Compared with earlier dual-AAV and triple-AAV systems, AAVLINK demonstrates higher fidelity gene reassembly and markedly reduced production of truncated or aberrant proteins—an issue that has hampered prior AAV split-vector gene therapies.

In vivo validation highlighted the therapeutic potential of this next-generation AAV platform. In a mouse model of Phelan-McDermid syndrome, AAV-mediated delivery of the oversized SHANK3 gene restored meaningful behavioral and motor function. In a severe epilepsy model of Dravet syndrome, AAV-based SCN1A gene replacement significantly extended survival, reduced seizure burden, and normalized neuronal activity—outcomes rarely achieved with previous AAV gene therapy strategies.

Translation potential was further supported by successful AAVLINK delivery in nonhuman primates, where robust AAV-driven gene expression was observed in the brain at levels comparable to murine studies. These results suggest that large-gene AAV therapies may be feasible in clinically relevant settings.

To accelerate broader adoption, the researchers generated an extensive AAVLINK vector library, encompassing 193 disease-associated genes and multiple AAV-compatible CRISPR gene-editing systems. All constructs were validated for correct gene reassembly and expression, positioning the platform as a scalable solution for AAV gene therapy pipelines.

A second-generation system, AAVLINK 2.0, further enhances safety by accelerating degradation of residual Cre recombinase, addressing long-term concerns around persistent non-human proteins in AAV-transduced cells.

Although clinical translation will require additional large-animal studies, dose optimization, and long-term safety evaluation, this advance represents a meaningful inflection point for the AAV field. By effectively expanding AAV cargo capacity, AAVLINK could unlock AAV gene therapies for hundreds of genetic diseases previously considered unreachable with standard AAV vectors.