ADENO-ASSOCIATED VIRUS VIRIONS AND METHODS OF USE THEREOF

ADENO-ASSOCIATED VIRUS VIRIONS AND METHODS OF USE THEREOF

Researchers at UC Berkeley And. UCSF have developed a recombinant adeno-associated virus (rAAV) virion, comprising a variant AAV capsid protein, which can exhibit greater infectivity of a macrophage and has potential therapeutic applications.

Adeno-associated virus (AAV) belongs to the Parvoviridae family and Dependovirus genus, whose members replicate upon co-infection with a helper virus such as adenovirus. AAV can establish a latent infection in the absence of a helper. The 4.9 kb single-stranded AAV genome is composed of two open reading frames encoding four regulatory proteins essential for viral replication and three structural proteins that encode the 60-mer capsid shell. The capsid mediates the ability of AAV vectors to overcome many of the cellular barriers to viral transduction, including cell surface receptor binding, endocytosis, intracellular trafficking and unpackaging in the nucleus.

Stage of Research

The inventors have developed the recombinant rAAV virion that exhibits greater infectivity of a macrophage, compared to a control with a wild-type capsid, as well as methods for delivering a gene product to a target macrophage using the rAAV virion. The rAAV virion is comprised of a variant capsid protein that confers an increased ability to infect macrophages, and the capsid can contain a heterologous nucleic acid sequence encoding one or more heterologous gene products. The gene product can be a polypeptide or an interfering RNA, an aptamer, or a gene-editing polypeptide. Delivery of such gene products to a macrophage can provide a treatment for an inflammatory disease, cancer, or other conditions. The inventors have also developed methods to administer an rAAV virion to an individual in need with the potential to treat various maladies, including neurodegenerative disease, a spinal cord injury, a traumatic brain injury, cancers including CNS tumors, human immunodeficiency virus infection, and leukodystrophies. The method that the inventors have developed includes, but is not limited to, administering an effective amount of rAAV virion via intracranial or intravenous injection.

Applications

Treating disorders of the central nervous system by delivering one or more polypeptides that provide an anti-inflammatory effect.
Treating traumatic brain injury and spinal cord injury.
Treating cancer by delivering one or more polypeptides that provide an anti-tumor effect.
Treating leukodystrophy.

Advantages

Greater infectivity of macrophages of the rAAV virion than a wild-type capsid containing virion, thereby offering greater infiltration of the tumor microenvironment.

Stage of Development

Research – in vitro

Publications

WO2022/087104