Adeno-associated viruses (AAVs) are small, non-disease-causing viruses that can be repurposed for medical use. Different versions, called serotypes, have distinct properties. Adeno-Associated Virus Rhesus Serotype 10 (AAVrh10), originally identified in rhesus macaques, is engineered as a vector to transport genetic material into cells for gene therapy.
Gene therapy aims to treat diseases by delivering a functional gene to cells that have a defective one. The AAVrh10 vector helps correct genetic problems at their source, offering the potential for long-term effects from a single administration.
The Mechanism of AAVrh10 in Gene Therapy
To be used as a gene therapy vector, the AAVrh10 virus is modified. Scientists remove its native genetic material, creating an empty protein shell called a capsid that cannot replicate or cause disease. This empty capsid is then filled with a functional version of a human gene needed to treat a specific disease.
Once prepared, the modified AAVrh10 vector is administered to a patient through an injection or infusion. The vector travels to its target cells, where the capsid is recognized by specific surface receptors, allowing it to enter.
Inside the cell, the vector navigates to the nucleus and releases its therapeutic gene. This new genetic material typically does not integrate into the host cell’s chromosomes. It remains as a separate, stable piece of DNA called an episome, allowing the cell to produce the necessary protein over a long period without permanently altering the original genome.
Key Properties and Advantages
AAVrh10 is selected for gene therapy based on several biological properties. A primary advantage is its broad tropism, or its ability to target a wide variety of tissues. It can efficiently transduce skeletal muscle, cardiac muscle, and the liver.
Another feature is its capacity to target the central nervous system (CNS), which includes the brain and spinal cord. It can cross the blood-brain barrier, a protective membrane that normally blocks substances from entering the brain. This ability allows it to be used for treating neurological disorders that were previously difficult to address with biologic drugs.
Compared to other AAV serotypes, AAVrh10 has a lower immunogenic profile. This means fewer people have pre-existing antibodies that would neutralize the vector before it delivers its therapeutic payload. This lower rate of pre-existing immunity increases the number of patients eligible for treatments using this vector.
Therapeutic Applications
The properties of AAVrh10 make it a primary vector for developing treatments for monogenic disorders, which are diseases caused by a single gene mutation. It is actively investigated in clinical trials for several severe genetic conditions. For example, it is used in therapies for Spinal Muscular Atrophy (SMA), a disease affecting motor neurons, where it delivers a functional gene to restore muscle function.
The vector’s muscle tropism also makes it suitable for treating conditions like Pompe disease and various forms of muscular dystrophy. In Pompe disease, a missing enzyme leads to glycogen buildup in muscle cells. Gene therapy with AAVrh10 aims to deliver the gene that produces this enzyme, improving muscle and respiratory function.
Beyond these examples, AAVrh10 is explored for other metabolic and neurodegenerative diseases. Research has demonstrated its potential in treating conditions like Globoid cell leukodystrophy (Krabbe disease). Ongoing clinical studies continue to explore new ways to target the genetic root of these illnesses.
Safety and Immune Considerations
A primary challenge in using AAVrh10 is the potential for a patient’s immune system to interfere. Some individuals have pre-existing neutralizing antibodies (NAbs) from natural exposure to similar viruses. These NAbs can recognize the AAVrh10 capsid and neutralize it, rendering the therapy ineffective.
For this reason, patients are screened for NAbs before receiving an AAV-based gene therapy. The presence of high levels of these antibodies can make a patient ineligible for treatment.
The immune system can also mount a response after the therapy is administered by recognizing the capsid as a foreign substance. This post-treatment immune response is closely monitored in clinical trials. Managing this response is part of ensuring the long-term safety and durability of the treatment.