The 4 Elements of an AAV-mediated gene replacement therapy

AAV-mediated gene replacement therapy (GRT) requires the inclusion of 4 critical elements:


A nonreplicating adeno-associated virus (AAV) vector

  • A nonpathogenic, nonmutagenic viral capsid is commonly used to efficiently transduce the target cells1-3
nonpathogenic, nonmutagenic viral capsid
functional transgene

The right gene that provides a therapeutic effect

  • A transgene contains functional genetic material that successfully codes for the desired protein3,4

Technology that allows for DNA replication upon entry into the nucleus

  • Self-complementary DNA technology, which is designed to not incorporate genetic material into the host genome, is engineered into the viral vector to increase transduction efficiency and enable rapid onset of action3,5,6
self-complementary DNA
a continuous promoter

An element that initiates target protein production

  • Coded elements, such as a continuous promoter, can activate the transgene upon entry into the cell nucleus and initiate gene expression3,7

A Closer Look at AAVs

The success of a GRT depends greatly on the delivery system, and several different vector systems have been developed and extensively studied to optimize the delivery process.1

Adeno-associated viruses (AAVs) have emerged as favorable vectors for GRT because they have been shown to:

  • Transfer genetic material into the nucleus and initiate transgene expression1
  • Enter dividing and nondividing cells with minimal immune response1
  • Target a variety of cells, including those of the liver, kidney, eye, and central nervous system (CNS)1

Choosing the Right AAV Serotype

The selection of a specific AAV serotype is dependent on the targeted disease, as each serotype presents with different properties, including tissue tropism, levels of transduction, and onset of action.1

Properties of AAV Serotypes1

Tissue tropisms of adeno-associated virus (AAV) serotypes and potential applications. Target tissues include those of the CNS.
Level of
Onset of Action

Potential Clinical Applications

  • Pompe disease
  • Eye disorders including retinal dystrophies*8
  • Neurodegenerative disorders
  • Lysosomal storage disorders
  • Eye disorders
  • Motor neuron diseases
  • Glycogen storage disorders
  • Neurodevelopmental disorders
  • N/A

*Indicates approved therapy

The Potential to Break Barriers

As certain AAVs, such as AAV9, can cross the blood-brain barrier, they may be able to treat monogenic CNS diseases with widespread neuronal transduction within the spinal cord and motor cortex.9

The Future of AAV-mediated GRT

AAVs have been clinically studied for over 25 years, and numerous ongoing studies are being conducted to evaluate the efficacy of AAV-mediated GRTs. Given the potential of adverse events, including immune responses to the AAV vector, safety is also being closely assessed in these studies.2,10

AAV-mediated GRT has the potential to deliver new treatment opportunities for a range of monogenic diseases, and advancements in the field of GRT may bring new possibilities to communities of patients, caregivers, and physicians around the world.1,10,11