Precision gene therapy for brain disorders: not there yet, but getting closer.
Press Release: August 24th, 2020
There are numerous disorders which affect the human brain, burdening millions of people worldwide. These include neurodegenerative disorders such as Alzheimer's and Parkinson's, primary and secondary brain cancers, stroke, epilepsy, among others. These conditions drastically decrease quality of life and can be fatal, while treatment options are currently limited or, more often, non-existent. A major obstacle in generating therapeutics for these disorders is the blood-brain barrier. The blood-brain barrier separates the brain from the main circulation of the body, protectively blocking the vast majority of substances in the circulation from reaching the brain. Without invasive intracranial injection, the vast majority of drugs do not reach the brain.
To overcome the obstacle of the blood-brain barrier, researchers are working on engineering viral vectors, such as adeno-associated virus (AAV), to increase their ability to reach the brain following non-invasive intravenous injection. Normally, viruses infect cells and release their own genetic material (either DNA or RNA) for the replication of more virus, as is typical of the pathogenic viral life cycle. The DNA carried by AAVs can be removed and replaced with DNA for a desired gene therapy. This not only makes AAV non-pathogenic, but also transforms it into a delivery vehicle for various gene therapies. Furthermore, the outer surface of the AAV capsid can also be modified to interact with different cellular receptors for entry into specific cells - much like a lock and key.
Previous research in mice has demonstrated that specific modifications of the outer surface of the AAV capsid greatly increase the ability of AAV to cross the blood-brain barrier and deliver the desired gene therapy to the brain. These capsid modifications are performed by editing the genes which encode the viral capsid proteins. The drawback is that the specific AAV capsid modifications from previous research only work in mice, but do not work when tested in non-human primates. In the context of the lock and key analogy, the mouse and human blood-brain barriers are differing locks which consequently require different keys for entry.
Research by STEM Biomedical colleagues Alexander Ille, Raoul Bodea, Anetta Ille, and collaborating peers aims to extend the ability of engineered AAVs to cross the blood-brain barrier beyond only working in mice. This research was recently published in the Journal of NeuroVirology, part of Springer Nature (Ille et al., 2020). The goal of this research is to advance efforts for engineering an AAV capable of efficiently crossing the blood-brain barrier for safe and effective gene therapy applications in humans. Although the research is still in an exploratory stage, progress is being made.
Through the use of various bioinformatic tools, the researchers identified a receptor in the human blood brain barrier which appears to be similar to the receptor responsible for the improved transport of AAV across the mouse blood-brain barrier. This data was used to computationally engineer AAV for crossing the human blood-brain barrier by a similar receptor mechanism as in mice. Simulations of binding between this engineered AAV and the desired human receptor appear promising, yet further research is needed. Despite the preliminary nature of the study, the researchers hope their work will help accelerate the development of successful therapeutic strategies for combating disorders of the brain.
Ille, A. M., Kishel, E., Bodea, R., Ille, A., Lamont, H., & Amico-Ruvio, S. (2020). Protein LY6E as a candidate for mediating transport of adeno-associated virus across the human blood-brain barrier. Journal of NeuroVirology. https://doi.org/10.1007/s13365-020-00890-9