Inside the World's First Neural Stem Cell Trial for Huntington Disease

Huntington disease (HD) remains one of the most devastating and treatment-resistant neurological conditions, with no therapy yet shown to meaningfully slow its progression. A few months ago, UCI Health administered the world's first intervention in REGEN4HD, a phase 1b/2a clinical trial evaluating hNSC-01, an embryonic stem cell-derived neural stem cell therapy delivered directly into the striatum using MRI-guided stereotactic navigation. The trial plans to enroll 21 people with early-stage HD, and the first patient has not reported any serious adverse events.

The trial is the result of more than 12 years of research and eight years of clinical planning at the University of California, Irvine, supported by a $12 million grant from the California Institute for Regenerative Medicine. NeurologyLive spoke with three members of the team behind REGEN4HD: Leslie M. Thompson, PhD, Donald Bren Professor of psychiatry and human behavior, as well as neurobiology and behavior, at UC Irvine and clinical trial sponsor; Ravi Rajmohan, MD, UCI Health neurologist and principal investigator; and Jefferson W. Chen, MD, UCI Health neurosurgeon who delivered the first intervention.

In this Q&A, the team discusses the scientific rationale behind using embryonic stem cell-derived neural stem cells, what sets this approach apart from other cell and gene therapies in development, how the MRI-guided surgical delivery system was designed, and what a favorable safety readout could mean for the future of Huntington disease treatment.

NeurologyLive: Can you discuss the rationale behind using embryonic stem cell-derived neural stem cells for Huntington disease, and what differentiates this approach from other cell or gene therapies currently in development?

Thompson: The rationale for using embryonic stem cell-derived neural stem cells as a treatment is their ability to differentiate into multiple cell types which may prolong neuron survival but also may provide cellular restoration of lost circuitry and replacement of lost cells.This is different than other approaches to transplant specific cell type progenitors. In preclinical studies in HD mouse models, we observed significantly improved HD relevant outcomes at the behavioral, molecular and electrophysiological levels, cells differentiated into several types of neuronal subtypes and notably produce brain derived neurotrophic factor.

As a first-in-human phase 1b/2a study, what are the primary safety and feasibility questions you hope to answer, and what early signals will you be monitoring beyond adverse events?

Rajmohan: The primary safety questions revolve around determining whether this method of treatment with neural stem cells will be safe for use in patients with Huntington’s Disease. Early signals we will monitor regarding feasibility relate to structured clinical assessments of participants’ neurological status and biomarkers from blood and cerebrospinal fluid samples.

The therapy is delivered directly into the striatum using MRI-guided stereotactic navigation. What advantages does this delivery approach offer, and what procedural challenges did the team need to overcome?

Chen: The MRI guided stereotactic navigation is key to placing the cells in the caudate and the striatum which are the areas in the brain that are affected by the Huntington's. These targets are just millimeters wide and in some cases millimeters in length.The MRI guidance system that we are using allows us to very precisely place the canula (a long and thin delivery tube) into the targets. We can visualize the canula placement to confirm it is where we want the cells to be deposited.

One of the challenges that we needed to overcome was to find the best positioning of the patient to allow us to target both the caudate and the striatum.As it turns out, this was done by placing the patient prone (laying on their stomach), intubated (on the breathing machine under anesthesia) in the 3 Tesla MRI machine. In addition to confirming the location of the canula, the use of the MRI guided stereotactic navigation system gives us real time feedback of any potential problems that may arise in the brain during the surgery.

Preclinical studies suggest hNSC-01 may protect neurons, replace lost cells, and restore trophic support. To what extent do you anticipate these mechanisms could translate into meaningful clinical benefit for patients?

Rajmohan: If these findings were to be reproducible in humans, this may offer significant benefits to patients by slowing the progression of the disease, by treating its symptoms, or both. This remains to be seen.

If the trial demonstrates favorable safety and preliminary efficacy, what would be the next steps for this program, and how do you see neural stem cell therapy fitting into the future treatment landscape for Huntington disease?

Rajmohan/Thompson: If this trial demonstrates favorable results, consideration will be given to applying for a multi-site phase 3 clinical trial to assess the reproducibility and generalizability of these observations. It remains to be seen how neural stem cells may shape the treatment of Huntington’s Disease, whether as a singular agent or as part of a multimodal treatment approach in combination with other approaches that target disease mechanisms.