How the Broad Institute innovated and developed a gene therapy for treating brain diseases.
At BB&N, one of the memorable moments of 9th-grade biology is the class discussion on CRISPR — a specific gene editing technique that modifies the DNA of a living organism. Though many people are familiar with CRISPR, it is just one of many gene therapies that researchers use to modify genetic information (1). Specifically, researchers at the Broad Institute, a premier research institution in Cambridge, are studying different diseases and the gene therapy vehicles/techniques that will treat such diseases (2). Though certain gene therapies have been successful when treating diseases in certain parts of the body, brain disease treatments have proven to be a challenge. Fortunately, today, the Broad Institute has discovered promising new methods to treat and prevent brain disorders such as Alzheimer’s, Huntington’s, and schizophrenia.
The breakthrough that the Broad Institute has achieved within murine (mouse) models is a newly engineered adeno-associated virus (AAV) that can efficiently cross the blood-brain membrane barrier to deliver genetic information. Usually working in conjunction with CRISPR technology, the AAV is used as a vehicle, also known as a vector, to deliver genetic modification components. Retaining the outer protein structure of a virus, the AAV has certain viral properties that allows it to enter into cells and nuclei. Though structurally similar to its preceding virus, the AAV’s replaced therapeutic genetic material is used as a substitute for the virus’s DNA. As a result, the AAV is unable to spread disease while being able to take advantage of the viral disguise to enter cells (3). Once entered into a cell through endocytosis, the process where cells take in extracellular material, the AAV can then travel to the nucleus, where it releases its DNA, ultimately leading to gene expression.
The process of gene therapies through an adeno-associated virus. https://www.genome.gov/genetics-glossary/Gene-Therapy#:~:text=Definition,healthy%20version%20of%20that%20gene.
In the past, the FDA-approved forms of AAVs have been unsuccessful in treating brain diseases, as they are unlikely to cross the blood-brain membrane. Due to the highly selective permeability of the blood-brain barrier, which protects the brain from harmful substances like certain molecules and viruses, the previous AAVs were unsuccessful when crossing that barrier (4). This was until researchers at the Deverman Lab at the Broad Institute found a breakthrough through tests within humanized mice — genetically modified mice with human tissues, organs, and genes. These researchers noticed that there were many human transferrin receptors expressed within the blood-brain barrier, so they modified their AAV to bind to those transferrin receptors. The result was a new AAV that was more likely able to cross the barrier and reach important brain cells like neurons and astrocytes (5). With the ability to reach different types and levels of cells within the brain, the researchers are optimistic that this procedure can carry the genetic material that will replace the mutated DNA that causes Alzheimer’s, Huntington’s, and schizophrenia, correcting the genetic error.
Despite these hopeful outcomes and bright futures, there are still questions regarding the ethics behind gene therapy, such as who decides the “normal” trait, whether these therapies ultimately destroy diversity within the world, and whether gene editing could play as an unfair advantage in athletics. Nevertheless, future innovations and findings within the field of gene therapy will turn previously untreatable diseases and disorders into preventable and treatable ones, allowing the possibility for people to choose whether or not they want to alter their biological identity and genome.
Cites:
- Center. (2020). What is Gene Therapy? U.S. Food and Drug Administration. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy
- Delivering gene-based therapies. (2023, September 13). @Broadinstitute. https://www.broadinstitute.org/delivering-gene-based-therapies
- Adeno-Associate Virus (AAV) for Gene Therapy | AskBio. (2024, November 16). AskBio. https://www.askbio.com/aav-gene-therapy/
- New gene delivery vehicle shows promise for human brain gene therapy. (2024, May 16). @Broadinstitute. https://www.broadinstitute.org/news/new-gene-delivery-vehicle-shows-promise-human-brain-gene-therapy
- Study finds surprising way that genetic mutation causes Huntington’s disease, transforming understanding of the disorder. (2025, January 16). @Broadinstitute. https://www.broadinstitute.org/news/study-finds-surprising-way-genetic-mutation-causes-huntingtons-disease-transforming