First participant dosed in pioneering neural stem cell trial for Huntington’s disease

Huntington’s disease (HD) involves the loss of cells in the striatum, an area of the brain that plays important roles in movement, cognition, and behaviour. For decades, researchers have been exploring a therapeutic approach that seems intuitive: is it possible to replace or support the vulnerable brain cells that are lost as HD progresses? This strategy, known as cell transplantation, aims to restore or reinforce the brain circuits affected by HD.

A new clinical trial testing neural stem cell transplantation for HD has reached an important milestone: the first participant has now received the experimental treatment. The study, called REGEN4HD, represents the first time this particular therapy, called hNSC-01, is being tested in people with HD.

While the trial is primarily designed to assess safety, it represents a significant step forward for this therapeutic approach. Let’s get into the details of the new study. 

What is hNSC-01?

hNSC-01 is a neural stem cell therapy. Neural stem cells are immature cells that can develop into the specialized types of cells that make up the brain and nervous system. Researchers hope that transplanted stem cells might help repair damaged brain circuits, provide support to existing nerve cells, or potentially replace some of the cells that are lost over the course of HD.

The cells will be implanted directly into the striatum, a deep brain region that is one of the earliest to be impacted in people carrying the HD gene change.

The idea behind this treatment is that the transplanted neural stem cells might replace lost neurons in people with HD. They could also release supportive factors that can help protect existing brain cells, reduce inflammation, or improve communication within brain networks. 

A first-in-human study

Because this study is the first time hNSC-01 has been given to people, the main goal is not to determine whether this treatment works, but whether it is safe for people with HD.

The Phase 1b/2a study plans to enroll 21 participants between the ages of 18 and 65 who have genetically confirmed HD. All participants will receive the treatment; there is no placebo group at this stage.

Researchers will gradually increase both the extent and dose of treatment across four groups (known as study cohorts) in the Phase 1b portion of the trial:

• Cohort A will receive a low dose in one side of the brain.
• Cohort B will receive a low dose in both sides of the brain.
• Cohort C will receive a medium dose in both sides of the brain.
• Cohort D will receive a high dose in both sides of the brain.

This stepwise approach is common in early-stage clinical trials and allows researchers to identify potential safety concerns before moving to higher doses or treating more people. 

The Phase 1b is followed by a Phase 2a to test what dose might be safest for people being treated, as well as early whether the treatment can improve signs and symptoms of HD. 

The study is being conducted at the University of California, Irvine through the UCI Alpha Clinic, with support from the California Institute for Regenerative Medicine (CIRM). The trial is led by Professor Leslie Thompson, a long-time HD researcher.

What will researchers measure?

The primary focus of the trial is safety and tolerability. Investigators will closely monitor participants for possible side effects related to both the implanted cells and the surgical procedure used to deliver them into the striatum – anything from immune reactions and altered blood work to neurological changes and physical falls. Safety will be assessed closely in the first several weeks after surgery, with longer-term follow-up extending to at least one year. 

Although the study is not designed to prove effectiveness, researchers will also look for early hints of hNSC-01’s effects on HD biology by collecting a wide range of exploratory measurements.

These include measures of movement symptoms using the Unified Huntington’s Disease Rating Scale Total Motor Score (TMS); assessments of daily function using Total Functional Capacity (TFC); thinking tests, including the Mini-Mental State Examination and Stroop Word Reading; detailed studies of brain structure using MRI and PET scans; and measurements of biomarkers in blood and cerebrospinal fluid (CSF). Among these biomarkers are neurofilament light chain (NfL), a marker of injury to brain cells, and proenkephalin (PENK), which is thought to more specifically reflect the health of neurons in the striatum that are particularly vulnerable in HD. 

Although these measures won’t provide definitive evidence that the treatment works, they may help researchers understand whether the transplanted cells might be influencing the progression of HD.

Why is this important?

Cell replacement and regenerative medicine approaches have long been viewed as promising strategies for HD, but they have also posed a challenge. Over the years, researchers have explored a variety of transplantation approaches, including foetal tissue grafts and fetal stem cells. Some earlier studies suggested that transplanted cells could survive in the HD brain, but technical, ethical, and practical challenges limited broader development.

Advances in stem cell biology and manufacturing have renewed interest in the field of transplantation for neurodegenerative disease. Modern approaches can produce more standardised cell products and are subject to rigorous quality control measures that were not available when earlier transplantation studies were launched. The REGEN4HD study is part of this new generation of regenerative medicine efforts so we are crossing our fingers for the best possible outcome. 

Cautious optimism

As exciting as this milestone is, it is important to keep ourselves grounded. Many experimental therapies that appear promising in lab studies do not ultimately become successful treatments. Early-stage trials are designed primarily to answer questions about safety, dosing, and feasibility, not how effective a therapy might be. 

The dosing of the first participant is perhaps best viewed as the beginning of a long process rather than the arrival of a new treatment. Researchers expect to collect the main data from the study by mid-2028, but participants will continue to be followed for several more years, with the full study expected to conclude in 2031. It will likely take several years before researchers have enough data to understand how safe hNSC-01 is in people and whether larger studies are justified.

Nonetheless, reaching the clinic is a very important achievement. Every new therapeutic strategy tested in people helps expand our understanding of HD and brings the field closer to effective treatments. For now, the HD community will be watching closely as the first brave participants begin this pioneering journey into neural stem cell therapy.

Summary: 

• The first participant has been dosed in REGEN4HD, a clinical trial testing a neural stem cell therapy called hNSC-01 in people with HD.

• hNSC-01 consists of neural stem cells that are implanted directly into the striatum, a brain region that is particularly affected in HD.

• Researchers hope the transplanted cells could support vulnerable brain cells, repair damaged brain circuits, or potentially replace some of the cells lost during disease progression.

• REGEN4HD is a Phase 1b/2a study enrolling 21 participants with HD. All participants will receive treatment, with doses gradually increasing across four study cohorts in the Phase 1b, followed by testing of the highest dose that appears safe in the Phase 2a.

• The primary goal of the trial is to determine whether the treatment and surgical procedure are safe and well tolerated.

• Researchers will also collect exploratory measures, including clinical assessments, brain imaging, and biomarkers such as NfL and PENK, to look for early signs of biological activity.

• Cell transplantation has been explored as a potential HD therapy for decades, but advances in stem cell technology and manufacturing have renewed interest in this regenerative medicine approach.

• While the first participant being dosed is an important milestone, the study remains at an early stage.