Gene and Cell Therapies for the Brain

Antisense drugs and AAV gene therapy for spinal muscular atrophy, ALS and rare disorders; stem-cell-derived dopamine neurons for Parkinson's; and the challenges of getting genetic medicines into the nervous system.

For most of history, neurological drugs targeted symptoms. Genetic medicine aims at causes, especially for single-gene disorders.

Antisense oligonucleotides

Antisense oligonucleotides (ASOs) are short, synthetic strands of nucleic acid that bind a gene's RNA message and change what happens to it — degrading it, or altering how it is spliced. Because they don't cross the blood-brain barrier well, they are often injected into the spinal fluid. Nusinersen (Spinraza), approved in the US in 2016, modifies splicing of the SMN2 gene to treat spinal muscular atrophy (SMA), a disease that kills motor neurons and was the leading genetic cause of infant death; treated babies can reach milestones like sitting and walking. Tofersen (2023) lowers the toxic SOD1 protein in a genetic form of ALS. Not all have succeeded: tominersen for Huntington's disease disappointed in 2021.

Viral gene therapy

Adeno-associated viruses (AAVs), harmless viruses stripped of their own genes, can deliver a working gene copy into cells. Onasemnogene abeparvovec (Zolgensma), approved in the US in 2019, delivers a functional SMN1 gene in a single intravenous infusion using AAV9, a version able to cross the blood-brain barrier in infants. In November 2024 the FDA approved eladocagene exuparvovec (Kebilidi) for AADC deficiency, a rare disorder preventing the brain from making dopamine and serotonin, delivered by direct infusion into the brain. Gene therapies for other childhood neurological disorders are in trials, along with an experimental AAV therapy for Huntington's disease that reported encouraging early results in 2025.

Cell replacement for Parkinson's

In the 1980s and 90s, surgeons transplanted fetal dopamine-producing tissue into the brains of people with Parkinson's disease, with mixed results and side effects. Today, researchers make dopamine neuron precursors from embryonic stem cells or induced pluripotent stem cells (iPSCs) — adult cells reprogrammed to an embryonic-like state, a technique for which Shinya Yamanaka shared the 2012 Nobel Prize. In 2025, two early-stage clinical trials (one in the US and Canada, one in Japan) published in Nature reported that transplanted stem-cell-derived cells survived, produced dopamine and appeared safe, with hints of benefit to be tested in larger trials.

Challenges

Delivering therapies across the blood-brain barrier, to enough cells, at the right dose, safely and affordably, is difficult. Some gene therapies cost millions of dollars per patient. Immune reactions to viral vectors and long-term safety need careful monitoring. Gene editing approaches such as CRISPR are being explored but are mostly at early stages for the brain.