Researchers Develop a New Way to Deliver Gene Therapies to the Brain

Scientists at the National Institutes of Health (NIH) have created a set of gene delivery systems that can reach different neural cell types in the human brain and spinal cord.

The new gene delivery tools can target key brain cell types, including excitatory neurons, inhibitory interneurons, striatal and cortical subtypes, brain blood vessel cells, and hard-to-reach neurons in the spinal cord. These could eventually be used to develop therapies for several diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy, as well as seizure disorders, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease and neuropsychiatric conditions.

“With these delivery systems, we can now access and manipulate specific cells in the brain and spinal cord — access that was not possible before at this scale,” John J. Ngai, Ph.D., director of the NIH’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, or The BRAIN Initiative, said in a news release.

The new tools use a small, stripped-down adeno-associated virus (AAV) to deliver DNA to target cells. AAV has been a component of many gene therapies that is used as a vector, or a way to carry and deliver the gene therapy to cells. Adenoviruses typically cause mild cold or flu symptoms and are considered safe for use in gene therapies.

AAV vectors have been used in some of the earliest gene therapies to be approved by the FDA, including Luxturna (approved in December 2017 to treat an inherited retinal disease) and Zolgensma (approved in May 2019 to treat spinal muscular atrophy.) More recently, AAV vectors have been used in Hemgenix, the first gene therapy approved in November 2022 for adults with hemophilia B, and Roctavian, which was approved in June 2023 as the first gene therapy for adults with hemophilia A.

Related: FDA Approves Gene Therapy for Debilitating Enzyme Deficiency

Last year, the FDA approved a gene therapy that can be administered directly to the brain. Developed by PTC Therapeutics, Kebilidi is an AAV gene therapy indicated for the treatment of adult and pediatric patients with AADC deficiency, a fatal, rare genetic disorder that typically causes severe disability. It is administered in four infusions in a single surgery through a stereotactic surgical procedure.

But the tools developed by NIH researchers have in mice been able to cross the blood-brain barrier. Theoretically, gene therapies developed with these tools could be given through intravenous infusion.

NIH researchers have created a set of enhanced AAV vectors that can target a broad selection of cells in the cortex, the outer layer of the brain. The new vectors have been optimized to increase efficacy and for diversified use, and they have been tested, or validated, in mice to cross the blood-brain barrier. These tools are available through public repositories, including Addgene and The Jackson Laboratory.

Funding issued less than four years ago launched a large-scale project to design new molecular tools. The Armamentarium for Precision Brain Cell Access specifically aimed to develop access to cells and circuits of the brain and spinal cord.

The BRAIN Initiative is a collaboration across 10 NIH institutes and centers. Part of the 21^st Century Cures Act, the initiative began in 2013 to develop partnerships to understand the brain and to accelerate the development of neurotechnologies. For fiscal year 2025, the initiative has a budget of $321 million. This, however, is a 20% decrease from FY 2024 as a result of lowered funding for the 21^st Century Cures Act.