Gene therapy seeks to modify or correct a defective gene within a patient’s cells to treat a genetic disorder at its root cause. This technique requires an effective delivery system, often accomplished using engineered viruses known as vectors. Adeno-associated viruses (AAVs) are the most widely utilized platform due to their favorable safety profile and ability to sustain long-term gene expression. Among the multitude of AAV variants, AAVrh10 has emerged as a particularly promising delivery vehicle. Derived originally from Rhesus macaques, AAVrh10 is now employed in cutting-edge research and clinical development for targeting difficult-to-reach tissues.
Understanding Adeno-Associated Viruses
Adeno-associated viruses are small, non-enveloped viruses belonging to the Parvoviridae family that naturally infect humans without causing overt disease. This non-pathogenic characteristic makes them highly suitable candidates for repurposing as delivery shuttles in gene therapy applications. The AAV structure consists of a protein shell, called a capsid, which encapsulates a single-stranded DNA genome of approximately 4.7 kilobases. The capsid’s specific surface features determine which cell types and tissues the vector can bind to and infect.
For therapeutic use, scientists genetically engineer the virus by removing its native viral genes and replacing them with a therapeutic gene cassette. This recombinant AAV (rAAV) vector retains the protective capsid and the ability to enter cells but is unable to replicate, ensuring its role is solely to deliver the genetic payload. Once delivered into the target cell’s nucleus, the single-stranded DNA genome is converted into a stable, double-stranded form that generally remains separate from the host cell’s chromosomes. This minimizes the risk of unwanted genomic disruption. This mechanism allows for long-lasting gene expression, particularly in non-dividing cells like neurons and muscle cells.
The Unique Properties of AAVrh10
AAVrh10 is designated as a serotype, meaning it possesses a distinct capsid structure that dictates its biological properties, including its preferred tissue targets and interactions with the immune system. This vector was initially isolated from Rhesus macaque tissue. The capsid structure of AAVrh10 is classified within clade E of AAVs and is closely related to a human variant, AAVhu.6, differing by only a few amino acids in the capsid protein sequence.
A key difference lies in the specific cellular receptor AAVrh10 utilizes for entry, which is distinct from many other common serotypes like AAV2 or AAV8. Research indicates that AAVrh10 binds to sulfated N-acetyllactosamine (LacNAc), a specific glycan structure found on the surface of certain cells. This distinct binding mechanism translates to a unique biodistribution profile. Furthermore, its specific capsid configuration may offer a degree of immune evasion compared to vectors derived from more common human isolates. This makes AAVrh10 a valuable alternative for patients who may have pre-existing antibodies against more widely used AAV serotypes.
Targeting Specific Tissues (Tropism)
The functional advantage of AAVrh10 is its distinct tropism, referring to its natural preference for transducing specific tissues and cell types. This serotype demonstrates high efficiency in targeting the Central Nervous System (CNS) and muscle tissues. AAVrh10 has shown the ability to cross the blood-brain barrier (BBB) after systemic delivery, a significant hurdle for many gene therapies aimed at neurological disorders. The ability to traverse the BBB allows for widespread gene delivery throughout the brain and spinal cord following a less invasive intravenous injection.
Within the CNS, AAVrh10 exhibits favorable cellular tropism, demonstrating high transduction rates in neurons, astrocytes, and oligodendrocytes compared to other serotypes. This broad cellular targeting is useful for treating complex neurological disorders that affect multiple cell types simultaneously. Beyond the nervous system, AAVrh10 also shows strong tropism for skeletal muscle and heart tissue. This dual-tissue affinity positions AAVrh10 as a versatile vector for systemic delivery applications affecting the neuromuscular system.
Current Applications in Gene Therapy
The robust tropism of AAVrh10 for the CNS and muscle has made it a vector of choice for numerous clinical development programs targeting severe genetic disorders. Its utility is evident in the treatment of lysosomal storage disorders that affect the brain and nervous system. For instance, AAVrh10 has been used in clinical trials targeting Batten disease, a neurodegenerative disorder, by delivering a functional copy of the deficient gene directly to the CNS. The vector is also being investigated for Metachromatic Leukodystrophy, carrying the gene for the enzyme Arylsulfatase A (ARSA) to correct the underlying defect. Given its strong muscle transduction, AAVrh10 has also been employed in trials for muscular dystrophies and certain forms of hemophilia.