From The Editor | June 29, 2022

UniQure's AAV Gene Therapy Trial for Huntington's Disease


By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1


uniQure is a gene therapy company advancing therapies for patients with severe medical needs. The company recently announced safety and biomarker data from 10 patients enrolled in the low-dose cohort of the ongoing Phase I/II clinical trial of AMT-130 for the treatment of Huntington’s disease. This is the first-ever AAV gene therapy trial for Huntington’s disease.

Six of the 10 patients were administered AMT-130 (via MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the brain) and four patients received an imitation surgery. Results showed mean reduction of 53.8% of mutant HTT (mHTT) versus baseline was observed in cerebral spinal fluid (CSF) 12 months after one-time administration of AMT-130. (Mutations in the HTT gene cause Huntington’s disease.) Measurements of CSF neurofilament light chain (NfL), a key biomarker of injury in the brain, increased as expected after surgery and returned to baseline levels at 12 months in three treated patients and remained slightly above baseline in the remaining patients. AMT-130 was generally well tolerated, with no serious adverse events reported after one year of follow-up.

I caught up with uniQure’s Matt Kapusta, CEO and Ricardo Dolmetsch, President of R&D to glean a better understanding of the Phase I/II trial.

Why was the clinical trial of AMT-130 blinded and randomized?

The FDA specifically requested that this Phase 1-2 trial be blinded and randomized so that it may be possible to observe any measurable differences between the treated and control patients.  FDA asked for a blind no shorter than 12 months. 

What was the anticipated outcome of the surgeries?

Based on our experience with preclinical animal models, we anticipated that the measurement of Nfl would increase following the surgery in the AMT-130 treated patients and that it would return close to baseline by 12 months.  We are very pleased with these results in the 6 treated patients. 

We also are very pleased to observe that AMT-130 has to date been well tolerated out to 12 months following dosing.  This is very meaningful as AMT-130 is a one-time administered, AAV-based gene therapy that is directly infused into the brain. 

We also are very pleased to observe a decrease in mHTT protein at 12 months in treated patients.  Based on data from the low dose of AMT-130 in the diseased pig model, we were not expecting to see a significant decrease in lowering of mHTT in the cerebral spinal fluid.  We believe these biomarker data support evidence of target engagement of AMT-130 that we hope we lead to clinical and functional benefit in the treated patients next year.

Briefly explain the “MRI-guided, convection-enhanced stereotactic neurosurgical delivery” into the brain.

Ricardo Dolmetsch, President of R&D: AMT-130 is delivered one time by convection-enhanced stereotactic injection directly into the striatum of patients. This route of delivery ensures that neurons in the striatum and in the cortex receive enough of the gene therapy to reduce the amount of the toxic protein.  The injection is performed using a catheter that is smaller than a cocktail straw which is introduced through a millimeter-scale burr hole in the skull. The infusion is performed with contrast enhancement using real time MRI guidance to ensure appropriate targeting. The surgery occurs over the course of a day and the patient typically returns home on the next day.

Matt Kapusta, CEO: AMT-130 is administered directly to the areas of the brain that are implicated in early manifest Huntington’s disease. During the procedure using MRI guidance, we can see real-time the infusion of AMT-130 filling the key brain structures. We believe this is absolutely crucial as no matter how effective a drug might be, it simply won’t be therapeutic if it can’t reach the diseased areas of the brain.

Explain Huntington’s disease as well as the ongoing trial.

Huntington’s disease is a progressive neurological disorder that represents one of the most devastating and prevalent monogenic diseases.  It is caused by a triplet nucleotide repeat within a single, mutated gene, called huntingtin, that leads to a toxic gain of function.

We believe AMT-130 has the potential to be not only a first, but best-in-class approach for the treatment of Huntington’s disease, and we are very pleased with the progress we are making across our clinical program to investigate this potentially groundbreaking gene therapy for the treatment of Huntington’s disease. 

AMT-130 continues to be generally well-tolerated through up to one year in the six treated patients from the low-dose cohort.  Thus far, there have been no significant adverse events associated with AMT-130 and mean neurofilament light chain levels are near baseline at 12 months. 

We are encouraged by the lowering of mutant huntingtin protein observed in the treated patients.  While this is a small number of patients, we believe these trends are early indications of target engagement.