Despite the recent FDA approval of antibody therapies such as Leqembi and Kisunla, which target amyloid plaques in the brain, there is still a pressing need for other treatment options for Alzheimer’s disease (AD). In particular, there is a need for treatments that do not rely on antibodies—treatments that could be used in combination with drugs like Leqembi and Kisunla to attack the disease from multiple angles. Gene therapy has emerged as one such promising approach in recent years. It works by introducing, replacing, or inactivating genes to treat or cure a disease. In the context of Alzheimer’s, these therapies could potentially deliver protective genes or silence harmful ones in brain cells. However, one of the most important factors determining the success of gene therapies is how they are delivered, because getting genetic material past the blood-brain barrier (BBB) and into the right cells is a significant challenge.
Adeno-associated viruses (AAVs) are harmless viruses that scientists have repurposed as delivery vehicles for gene therapy. Viruses are naturally skilled at entering cells and delivering genetic material, which makes them ideal delivery systems. To create an AAV delivery system, researchers remove the virus’s original genetic material and replace it with the therapeutic genes needed to address a patient’s condition. AAVs can even be designed to target specific cell types.
Despite the successful use of AAVs in studies involving animal models of AD, their application in human patients with neurodegenerative diseases has been less successful. This is, in part, due to difficulties crossing the BBB. The BBB has different molecular entry points (receptors) in humans compared to laboratory animals. AAVs designed to cross the barrier in animal models often can’t do the same in humans. To overcome this hurdle, Drs. Lisowski, Drouyer, and González-Aseguinolaza, all experts in developing and testing AAVs, are working to develop an AAV specifically capable of crossing the human BBB.
To achieve this, their project is divided into three primary aims. In the first, they will build a library of AAV capsids, which is the exterior shell of the AAV. They will focus on identifying capsids that bind receptors on the human BBB. This will first be done in cell culture models expressing human BBB receptors, where they will determine which AAVs are most capable of transport across the BBB. In parallel, those AAVs will be tested in a mouse model with a humanized BBB to confirm that they can, in fact, cross the BBB and enter the brain. The second aim will focus on determining the safety profile of the strongest candidates identified from the first aim. A common concern with AAVs is their tendency to bind in the liver and accumulate, leading to unintended side effects. As part of this aim, Dr. Lisowski and colleagues will screen their top candidates in human liver explants and in a mouse model transplanted with human liver cells (hepatocytes) to determine which AAVs are least likely to build up there. For the final aim, the strongest candidates from the first two aims will be tested in a non-human primate model to assess safety and efficacy. Their goal is to identify the strongest candidate AAV from these aims with the highest potential for use in humans.
This project aims to address one of the biggest hurdles in employing gene therapies against neurodegenerative diseases: the delivery system. By developing an AAV capable of crossing the human BBB, this expert team aims to enable the delivery of a wide range of potential gene therapies to combat AD and other conditions.
