Gene Therapy for Huntington's Disease

Recruiting at 2 trial locations

Overseen By Andrew Duker, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Spark Therapeutics, Inc.

Must be taking: Cholinesterase inhibitors, Antipsychotics

Must not be taking: Antisense oligonucleotides

Disqualifiers: Deep brain stimulation, Gene therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called SPK-10001 for individuals with Huntington's Disease. The goal is to determine the treatment's safety and its potential effectiveness in easing symptoms. Participants will either receive the gene therapy or undergo a placebo surgery, which involves a procedure without the actual treatment. This trial suits those diagnosed with Huntington's Disease confirmed by genetic testing and who face daily challenges, such as movement difficulties. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial requires that certain medications, like cholinesterase inhibitors, memantine, amantadine, riluzole, antidepressants, benzodiazepines, antipsychotics, and others for motor symptoms, must be at a stable dose for at least 12 weeks before starting the trial and remain stable during the first 12 months. If you are on these medications, you will need to keep your dose unchanged.

Is there any evidence suggesting that SPK-10001 is likely to be safe for humans?

Research has shown that SPK-10001 demonstrates promising safety results in studies for Huntington's Disease. Reports confirm that SPK-10001 safely reduces the harmful HTT protein linked to the disease, with effects that persist over time. This indicates the treatment continues to work without causing harm.

In these studies, participants generally tolerated SPK-10001 well, with most experiencing no serious side effects. This suggests the treatment might be safe for humans, but further testing will provide clearer answers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Huntington's Disease?

Unlike the standard treatments for Huntington's disease, which mainly aim to manage symptoms, SPK-10001 is a gene therapy that targets the genetic root of the condition. Most treatments for Huntington's focus on alleviating symptoms like movement disorders or mood swings, but SPK-10001 offers a potential to correct the underlying genetic defect. This innovative approach could lead to more lasting improvements and potentially halt disease progression, which is why researchers are particularly excited about it.

What evidence suggests that SPK-10001 might be an effective treatment for Huntington's Disease?

Research shows that SPK-10001, which participants in this trial may receive, might help treat Huntington's Disease by lowering levels of the protein huntingtin, linked to the disease's symptoms. Studies have found that SPK-10001 can safely and effectively reduce this protein's production in cells. This reduction is important because it may slow the disease's progression. Early findings suggest that SPK-10001 has a strong and lasting effect, promising for long-term treatment. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for individuals with Huntington's Disease who have specific motor and functional scores, stable medication use for certain conditions, and confirmed genetic markers. Participants must not be on fluctuating doses of medications like cholinesterase inhibitors or antipsychotics.

Inclusion Criteria

I've been on a stable dose of certain brain medications for 12 weeks and can keep the dose the same for the next 12 months.

My antidepressant or benzodiazepine dose has been stable for 12 weeks and will remain so after starting SPK-10001.

My functional ability score is 11 or higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time, bilateral, intraparenchymal infusion of SPK-10001 or placebo into the caudate and putamen

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, tolerability, and preliminary efficacy after treatment

12 months

Regular visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• SPK-10001

Trial Overview

The study tests the safety and potential benefits of SPK-10001 gene therapy compared to a placebo surgery control in people with Huntington's Disease. It aims to see if this new treatment can improve their condition.

How Is the Trial Designed?

Group I: SPK-10001 Experimental Treatment 1 Intervention

Group II: Placebo Surgery Control Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Spark Therapeutics, Inc.

Lead Sponsor

Trials

16

Recruited

410+

Published Research Related to This Trial

Using small interfering RNAs (siRNAs) to target the huntingtin gene in a mouse model of Huntington's disease led to a significant reduction in the expression of the harmful mutant protein, which is crucial for the disease's progression.

The treatment not only improved motor function and prolonged the lifespan of the mice but also slowed down weight loss, indicating that siRNA-based therapy could be a promising future approach for treating Huntington's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA. Wang, YL., Liu, W., Wada, E., et al.[2016]

A modified lentiviral vector carrying a small hairpin RNA (shRNA) effectively reduced the expression of the huntingtin protein in striatal neurons derived from induced pluripotent stem cells of Huntington's disease patients, showing promise for treating the disease.

In an in vivo rodent model, this vector not only decreased key pathological features of Huntington's disease but also triggered minimal inflammation, indicating a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing. Cambon, K., Zimmer, V., Martineau, S., et al.[2020]

The study introduces a new mouse model of Huntington disease (HD), called Hu97/18, which genetically mimics human HD by carrying two human HTT genes and no mouse Hdh genes, allowing for more accurate research into the disease.

This model exhibits key behavioral and neurological symptoms of HD, making it a valuable tool for testing therapies aimed at silencing the mutant huntingtin gene without affecting the normal HTT gene, which is crucial for neuronal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fully humanized transgenic mouse model of Huntington disease. Southwell, AL., Warby, SC., Carroll, JB., et al.[2021]

A systematic review identified nine phase III clinical trials for Huntington's Disease treatments, involving eight different drugs, including both FDA-approved medications and those still under investigation.

While there is currently no cure for Huntington's Disease, the review highlights ongoing efforts to develop therapies that can alleviate symptoms, with four of the drugs already approved for use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Huntington's Disease Drug Development: A Phase 3 Pipeline Analysis. Van de Roovaart, HJ., Nguyen, N., Veenstra, TD.[2023]

Convection enhanced delivery (CED) of small interfering RNA targeting the huntingtin gene (siHtt) in nonhuman primates resulted in widespread and significant suppression of the huntingtin protein, indicating a promising method for treating Huntington's disease.

The study demonstrated that this method was well tolerated by the brain, suggesting its potential safety for future therapeutic applications in humans with Huntington's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Stiles, DK., Zhang, Z., Ge, P., et al.[2016]

Huntington's disease (HD) is caused by a genetic mutation in the huntingtin (HTT) gene, leading to severe neurodegeneration and symptoms like involuntary movements and cognitive decline.

Current research is actively exploring various therapeutic options, including small molecules and molecular therapies, to treat HD, highlighting ongoing efforts in both preclinical and clinical development stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Strategies for Huntington's Disease. Mrzljak, L., Munoz-Sanjuan, I.[2016]

A phase I study involving 6 subjects with early-stage Huntington's disease demonstrated that intracerebral administration of ciliary neurotrophic factor (CNTF) is safe, with no signs of toxicity observed during the 2-year trial.

While some improvements in electrophysiological results were noted, the variable survival of CNTF-producing cells and low CNTF release in many cases highlight the need for technique enhancements to optimize therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Bloch, J., Bachoud-Lévi, AC., Déglon, N., et al.[2012]

A novel siRNA strategy was developed to specifically silence the harmful mutant huntingtin protein in Huntington's disease without affecting the protective wild-type huntingtin, showing efficacy in both HD fibroblasts and neuroblastoma cells.

This targeted approach not only reduced the activation of caspase-3, a marker of cell stress and apoptosis, but also holds potential for personalized genetic therapies for Huntington's disease and other similar genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allele-specific silencing of mutant Huntington's disease gene. Zhang, Y., Engelman, J., Friedlander, RM.[2021]

Sodium phenylbutyrate (SPB), a histone deacetylase inhibitor, was found to be safe and well-tolerated in humans with Huntington's disease at doses of 12 to 15 g/day, with the maximum tolerated dose being 15 g/day.

While SPB showed no significant laboratory or electrocardiographic abnormalities, higher doses led to toxicity symptoms like vomiting and confusion, indicating the need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium phenylbutyrate in Huntington's disease: a dose-finding study. Hogarth, P., Lovrecic, L., Krainc, D.[2013]

Huntington's disease (HD) is a promising target for gene therapy due to its single genetic cause, making it potentially easier to develop effective treatments compared to other movement disorders with multiple genetic factors.

Despite over 100 clinical trials for HD that have largely failed to provide significant benefits beyond symptom management, ongoing research into gene transfer methods and new experimental trials may offer hope for future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy for Huntington's Disease: The Final Strategy for a Cure? Byun, S., Lee, M., Kim, M.[2022]

AAV9-RNAi injections into the intrajugular vein significantly reduced levels of the toxic mutant huntingtin protein (mHTT) in multiple brain regions and peripheral tissues in a mouse model of Huntington's disease, suggesting a potential for widespread therapeutic effects.

This systemic delivery method not only prevented motor symptoms and brain atrophy but also addressed severe weight loss associated with Huntington's disease, indicating a promising approach for treating various symptoms of the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice. Dufour, BD., Smith, CA., Clark, RL., et al.[2021]

The study tested two different anti-Htt intrabodies, V(L)12.3 and Happ1, in five mouse models of Huntington's disease (HD), finding that Happ1 significantly improved motor and cognitive functions and reduced neuropathology across multiple models.

Happ1 not only improved symptoms but also extended the lifespan of N171-82Q mice, suggesting that it could be a promising gene therapy for preventing disease progression in HD, while V(L)12.3 showed mixed results and even worsened conditions in some models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease. Southwell, AL., Ko, J., Patterson, PH.[2022]

AAV-mediated RNA interference (RNAi) effectively reduced levels of both mutant and wild-type huntingtin protein by approximately 40% in the striatum of YAC128 mice, which model Huntington's disease.

This reduction in huntingtin levels was associated with significant improvements in behavioral deficits and a decrease in harmful protein aggregates, without causing notable neurotoxicity, suggesting a promising therapeutic approach for Huntington's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease. Stanek, LM., Sardi, SP., Mastis, B., et al.[2021]

The RNA interference approach using miHDS1 effectively reduced huntingtin (HTT) expression in Rhesus macaques without causing adverse neurological effects, indicating its potential safety for human application.

However, when tested in normal mice, miHDS1 caused acute neurological deficits due to off-target effects, highlighting the challenges of ensuring safety in animal models that are distantly related to humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. Monteys, AM., Spengler, RM., Dufour, BD., et al.[2021]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06826612

NCT06826612 | A Randomized Study of SPK-10001 Gene ...

Study Overview​​ The main goal of this study is to evaluate the safety, tolerability, and preliminary efficacy of SPK-10001 in participants with Huntington's ...

2.

huntingtonstudygroup.org

huntingtonstudygroup.org/study/spk-10001-101/

SPK-10001-101

This means that cells treated with SPK-10001 will have reduced levels of both normal and mutant huntingtin protein (mHTT) mRNA and protein.

3.

trialfinder.panfoundation.org

trialfinder.panfoundation.org/en-US/trial/listing/581115

A Randomized Study of SPK-10001 Gene Therapy in ...

The main goal of this study is to evaluate the safety, tolerability, and preliminary efficacy of SPK-10001 in participants with Huntington's Disease. Trial ...

4.

northernbiolab.com

northernbiolab.com/wp-content/uploads/2025/08/SPK-10001_GLP-tox-Poster-2024_NBR-display.pdf

SPK-10001 induces a durable and safe reduction of HTT ...

Results from terminal tissue analysis confirmed SPK-10001 durability and good dose-response throughout treatment, while quantification of SPK-10001 transgene ...

5.

withpower.com

withpower.com/trial/phase-2-huntington-disease-1-2025-ea331

Gene Therapy for Huntington's Disease

The main goal of this study is to evaluate the safety, tolerability, and preliminary efficacy of SPK-10001 in participants with Huntington's Disease. Show more.

6.

hdyo.org

hdyo.org/a/874-clinical-trials-in-hd

Clinical Trials in HD

This trial is assessing the safety, tolerability and preliminary efficacy of SPK-10001 in patients suffering from Huntington's Disease. SPK- ...