Huntington’s Disease

Steven Finkbeiner and his laboratory use neurons generated from Huntington’s patients’ stem cells, as well as animal models, to study how the mutant huntingtin protein affects brain cells over time. By tracking individual neurons with sophisticated imaging technologies, the team made a surprising discovery: protein aggregates known as inclusion bodies—once thought to contribute directly to disease—may actually represent a protective response that helps neurons cope with toxic mutant huntingtin. This finding reshaped scientists’ understanding of Huntington’s and opened new avenues for developing therapies that support the brain’s natural defense mechanisms.

Gladstone researchers, led by Finkbeiner, have built a fully automated, high-throughput platform known as the “Thinking Microscope” that can evaluate potential Huntington’s disease therapies across hundreds of thousands of patient-derived neurons. The system combines advanced imaging, a highly sensitive cell-death biosensor called GEDI2, and machine learning algorithms capable of distinguishing diseased neurons from healthy ones. Scientists can use this platform to rapidly test drugs and genetic interventions, identifying approaches that restore cells to a healthier state. The technology is also supporting collaborations with biotechnology companies developing next-generation Huntington’s disease therapies.

Not everyone with Huntington’s disease develops symptoms at the same age, even when they carry similar disease-causing mutations. Finkbeiner’s team is studying families with unusually early or late disease onset to identify genetic factors that influence progression. Using whole-genome sequencing and gene-editing technologies, Julia Kaye, Finkbeiner, and others have uncovered modifier genes that appear to protect neurons from damage. One promising modifier gene called OTUD3 may help cells clear toxic huntingtin proteins more effectively. By understanding how these naturally protective pathways work, scientists hope to develop treatments that are both effective and safe.

Many of the modifier genes that Gladstone scientists have identified are linked to biological pathways that already can be targeted with existing medicines. Researchers are investigating whether FDA-approved drugs and other compounds can influence these pathways and improve the health of Huntington’s disease neurons. Because these medicines have already undergone extensive safety testing, successful results could accelerate the path toward new treatment options for patients.

In addition to identifying drug targets, Gladstone scientists are searching for biomarkers—measurable biological signals that can track disease progression or predict treatment response. Several genes identified through the team’s studies, including a gene known as KALRN, show promise as biomarkers and may also represent new therapeutic targets. Better biomarkers could help researchers design more efficient clinical trials, identify patients most likely to benefit from specific treatments, and bring therapies to patients earlier in their disease.

As key members of the National Institute of Neurological Disorders and Stroke’s Huntington’s Disease iPSC Consortium, Finkbeiner and Kaye helped set the foundation for modeling Huntington’s using human stem cells. By turning patient stem cells into medium spiny neurons—the brain cells hardest hit by the disease—they created essential models containing the genetic CAG repeats that drive Huntington’s. This gives scientists an accurate platform to test potential drugs and identify treatments that could protect or save these neurons in actual patients.

Gladstone’s innovative approaches continue to reshape the field. In a seminal Nature paper, Finkbeiner revealed that protein clumps (inclusion bodies) actually protect neurons from mutant huntingtin. More recently, Gladstone researchers applied machine learning to explore CAG expansions, uncovering how the disease operates through both toxic gains of function and losses of normal protein activity.