Research Terms
Center for Structural Biology (Health Science Center)
| Director |
Robert Mckenna |
| Phone | 3522948393 |
| Website | http://www.csb.ufl.edu |
| Mission | The Center for Structural Biology fosters faculty collaboration in structural studies of significant biological problems to increase understanding of biological function and to provide advanced training for students in structural biology. Structural studies are accomplished using advanced spectroscopic, diffraction, and imaging techniques (NMR, optical microscopy, EM, and X-ray crystallography). This information is related to molecular structure, cellular structure and function; then to the morphology and physiology of the whole organism. |
Adeno-associated virus (AAV)-based vectors are the leading platform for the delivery of gene therapy in vivo, but have a limitation in that they need to avoid neutralizing and potentially dangerous immune response to the AAV capsids.
AAV9 is one of the most used AAV serotypes for therapeutic applications due to its ability to transduce multiple tissues and organs, such as cardiac and skeletal muscle, liver, pancreas and the eye, and its ability to cross the blood-brain-barrier, crucial for reaching the central nervous system. However, approximately 40% of the population presents pre-existing neutralizing antibodies against AAV9, making them ineligible for AAV9-based treatments. Additionally, the common occurrence of cross-reactivity between variants often results in the neutralization of more than one AAV serotype by the same antibody. The presence of these neutralizing antibodies in a patient receiving AAV-based gene therapy can decrease treatment effectiveness and have detrimental immunogenic responses.
Researchers at the University of Florida have engineered the AAV9 capsid, based on the binding profile of anti-AAV9 antibodies derived from patients who received a commercially available AAV9 biologic therapy. Common binding regions in the AAV9 capsids are modified to circumvent the detection of the new capsid variant by pre-existing neutralizing antibodies and enhance the therapy's effectiveness. By incorporating one or more mutations on the AAV capsid, these AAV particles can escape neutralizing human antibodies to treat patients who would otherwise be unable to receive treatment.
Recombinant AAV9-based vectors escaping neutralizing antibodies for more efficient and safer gene therapies
Adeno-associated virus 9 (AAV9)-based vectors are the main gene therapy delivery vehicle, and several AAV9-based therapies hold FDA approval. However, the presence of neutralizing human antibodies in a significant portion of the population limits their use. These antibodies target and neutralize specific AAV serotypes, and in some instances, several AAV serotypes, greatly decreasing the number of patients able to receive therapy.
Researchers at the University of Florida engineered the AAV9 capsid, harboring one or more mutations in VP1, VP2 and/or VP3. These mutations modulate reactivity to neutralizing antibodies, while maintaining or even increasing their infectivity and production and transduction efficiency. Evasion of neutralizing antibodies decreases immunogenic responses and improves efficacy. This can enable delivery of AAV9-based therapies to subjects testing positive for these antibodies, allowing more patients to receive gene therapy and participate in clinical trials.
These engineered AAV vectors are designed to target neuronal cell types to aid in the development of gene therapies, which can treat a variety of neurological diseases. In 2020, the market for CNS targeting technologies was worth $6 billion and is expected to reach $46.5 billion by 2030. Neurological diseases can result in life-threatening complications or lead to serious symptoms and/or death. Effective treatments remain limited. Gene therapies have the potential to treat individuals suffering or at risk for suffering from various neurological diseases and conditions.
Researchers at the University of Florida developed improved adeno-associated virus (AAV) vectors to target the central nervous system (CNS) for treatment of neuronal diseases and disorders.
AAV capsid modification that targets the central nervous system and other neuronal cell types to treat diseases that affect neurological tissue and/or function
University of Florida researchers have generated AAV capsids of the serotypes AAV1, AAV9 and AAVrh.10 containing a specific CNS-targeting protein insertion and have shown them to be effective at targeting different neuronal cell types, increasing transduction efficiency as much as 25 fold in certain circumstances. The insertion of the CNS targeting peptide also eliminates an immunogenic epitope, making the vectors less likely to be neutralized by the immune system.
