What You'll Learn
This article summarizes a recent research review on Huntington's disease (HD), focusing on the latest progress in gene and cell therapies. You’ll learn about what these treatments aim to do, which approaches are being tested, and what this means for people living with HD or at risk.
A Quick Look at Huntington's Disease
HD is a rare, inherited brain disorder caused by a faulty gene called HTT (short for "huntingtin gene"). Most people have 9–35 repeats of a DNA segment called "CAG" in this gene. In HD, this segment expands to 36 or more repeats, making an abnormal protein (mutant huntingtin, or mHTT) that damages brain cells over time.
Symptoms typically start in a person’s 30s–40s and worsen over 15–20 years. They include:
- Uncontrolled movements (chorea),
- Trouble thinking or remembering (cognitive decline),
- Mood swings, depression, or irritability (emotional changes).
Today, there’s no cure for HD—treatments like tetrabenazine or antidepressants help manage symptoms, but they don’t stop the disease from progressing.
Why This Research Matters
HD is caused by a single faulty gene, making it a prime target for gene and cell therapies—treatments that aim to fix or replace the problem at its source. This review brings together decades of research to explain what’s working, what’s not, and where scientists are heading next. For patients and families, this means understanding new hope on the horizon.
What Current Research Says About Gene and Cell Therapies
Gene Therapy: Targeting the Faulty Gene Directly
Gene therapies aim to lower levels of the harmful mHTT protein or fix the HTT gene. Here are the key approaches being tested:
1. Antisense Oligonucleotides (ASOs)
ASOs are tiny pieces of RNA that "silence" the faulty HTT gene, reducing mHTT production. They’re given via spinal fluid injections (intrathecal).
- Tominersen: An early ASO trial showed it lowered mHTT in spinal fluid but was paused in 2021 due to mixed results. A new trial (GENERATION HD2) is now testing lower doses in younger patients with early symptoms.
- WVE-003: A newer ASO that targets a specific genetic marker (SNP) in 40% of HD patients. Early results show it safely reduces mHTT and may reach deeper brain areas.
2. RNA Interference (RNAi)
RNAi uses viruses to deliver genetic material that "turns off" the HTT gene.
- AMT-130: Given via surgery directly into the brain (striatum), this therapy showed early signs of slowing symptom progression in small trials, though high doses caused temporary side effects.
3. Small-Molecule Drugs
These oral medications cross the blood-brain barrier to block mHTT production.
- PTC518: A pill that lowers mHTT levels. Early trials suggest it’s safe, but more data is needed to confirm if it slows disease.
4. Gene Editing (CRISPR/Cas9 and Others)
Tools like CRISPR act like "molecular scissors" to cut out or repair the faulty HTT gene. While promising in animal studies, these are still early-stage and face challenges with safety and delivery to the brain.
Cell Therapy: Replacing Damaged Brain Cells
HD destroys cells in the striatum (a brain region critical for movement and thinking). Cell therapies aim to replace these cells or protect remaining ones.
1. Stem Cells and Progenitor Cells
- Neural Stem Cells (NSCs): Lab-grown cells that can turn into brain cells. Early studies in mice show they may repair damage, but human trials are just starting.
- Mesenchymal Stem Cells (MSCs): These cells, often from bone marrow or umbilical cord blood, secrete proteins that protect brain cells. Trials like NestaCell (using dental pulp stem cells) are testing if they slow symptom decline.
2. Fetal Cell Transplants
Early trials used fetal brain cells to replace lost neurons, but results were mixed, and ethical concerns limit this approach today.
What This Means for Patients and Families
- Hope, but patience: Many therapies are in clinical trials, but it will take years to know if they’re safe and effective. Not all will work—some (like Tominersen) have faced setbacks.
- Early intervention matters: Most trials focus on people with early symptoms or at high risk (before symptoms start). Talk to your doctor about trial eligibility.
- Symptom management still key: Even with new therapies, current treatments for chorea, mood, and cognition remain important for quality of life.
Gaps in Knowledge & Future Directions
Scientists are working to solve big challenges:
- Delivery: Getting therapies to deep brain regions (like the striatum) without causing side effects.
- Specificity: Targeting only the faulty HTT gene to avoid harming the healthy version.
- Late-stage disease: Most therapies work best before severe brain damage—new approaches are needed for advanced HD.
- Combination therapies: Mixing gene editing with cell transplants or other drugs to boost effectiveness.
Key Points to Remember
- HD is caused by a faulty HTT gene with too many CAG repeats, leading to brain cell damage.
- Gene therapies (ASOs, RNAi, CRISPR) aim to lower harmful mHTT or repair the gene.
- Cell therapies try to replace lost brain cells or protect remaining ones.
- Most new therapies are in trials—ask your doctor about options.
- Progress is slow, but research is active, offering hope for better treatments.
Talk to Your Doctor
Every person with HD is different. Use this information to ask your healthcare team:
- Am I eligible for any clinical trials?
- How can I manage symptoms while waiting for new therapies?
- What should my family know about genetic testing or risk?
You don’t have to navigate HD alone—your care team, support groups, and researchers are all working toward better outcomes.
This article is based on "Advances in gene and cellular therapeutic approaches for Huntington’s disease" (Protein Cell, 2024).