UniQure’s Gene Therapy AMT-130 for Huntington’s Shows Promising Results in Preclinical Studies

AMT-130, uniQure’s experimental gene therapy candidate for Huntington’s disease, halts shrinkage of certain brain regions and helps preserve cognitive function in a mouse model of the disease, preclinical data show.

Additionally, a single dose of AMT-130 reduced the levels of mutated huntingtin (HTT) — the protein that is involved in Huntington’s — by 68% in patient-derived neuronal cells.

“The data provide further support for the potential safety and efficacy of AMT-130 and we remain excited to advance our recently initiated Phase I/II clinical trial of AMT-130 in patients with Huntington’s disease,” Sander Van Deventer, MD, PhD, executive vice president of research and product development at uniQure, said in a press release.

The trial (NCT04120493), currently recruiting participants, will randomly assign patients at the early stages of the disease to receive escalating doses of a one-time treatment with AMT-130. More information on trial contacts and recruiting sites is available here.

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene, which leads to the production of a mutated form of the huntingtin (mHTT) protein that is prone to aggregation.

AMT-130 is an experimental gene therapy that works by inhibiting the production of mHTT. It does this by carrying a small molecule, called microRNA, that binds to and destroys the messenger molecule carrying instructions for the production of the huntingtin protein. As a result, AMT-130 lowers the levels of the defective huntingtin protein. Of note, microRNAs are tiny RNA molecules that control the expression of several genes; RNA molecules are the templates used by cells to produce proteins.

Researchers tested the efficacy and tolerability of AMT-130 in a mouse model of Huntington’s in a study, “Potent and sustained Huntington’s lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease,” published in the journal Nucleic Acids Research.

These mice, known as Hu128/21, carry a normal and a mutated copy of the human HTT gene and spontaneously develop symptoms resembling those experienced by patients with Huntington’s.

At two months of age, mice were injected with a saline solution (control) or one of three ascending doses of AMT-130 — 5.2×10⁹ (low), 2.6×10¹⁰ (medium), or 1.3×10¹¹ (high) genome copies per mouse — into the striatum, a brain region involved in motor control.

To track the distribution of the gene construct, the AAV5 viral vector was labelled with a green fluorescent protein. The researchers found that AAV5 was broadly spread in the animals’ brains, particularly in the striatum, hippocampus, and cortex region, all regions that are commonly affected by the disease.

Of note, the hippocampus is a brain region responsible for short-term memory, and the cortex is the outer layer of the brain that controls awareness, perception, attention, and memory.

Treatment led to a significant reduction in the levels of both healthy and mutated forms of HTT. The reduction was dose-dependent, reaching 92% in the striatum and 64% in the cortex region, seven months after the injection with the highest dose tested.

The researchers then assessed treatment effects on motor coordination and balance using the rotarod test — a test in which animals must try to stay on a horizontal rod while it rotates.

Treatment did not lead to improvements in motor function. However, the animals had experienced a significant increase in body weight which could have influenced these results, indicating that Hu128/21 mice are likely unsuitable to study treatment effects on motor function.

Treatment effects on exploratory activity and anxiety-like behaviors were also evaluated using the open-field test seven months following treatment. Test results suggested that the highest dose of the therapy seemed to ease anxiety-like behavior.

Investigators also evaluated the treatment effects on cognition using the novel object-location memory test, which assesses spatial learning, seven months post-treatment.

Healthy mice usually show a preference for a known object in a novel location but “Hu128/21 mice have a spatial learning deficit and show no preference in object location from 6 months of age,” the researchers wrote. However, treatment with AMT-130 restored animals’ preference for a known object in a novel location, in a dose-dependent manner.

Next, the researchers investigated if treatment could prevent the shrinkage (atrophy) of the striatum, which is known to occur in Huntington’s, and observed that treatment with AMT-130 led to a dose-dependent increase in striatum volume.

The therapy, however, had no impact on the shrinkage of the corpus callosum (the area that connects the two sides of the brain), which is also observed in early Huntington’s.

The researchers reported that in healthy mice, the treatment reduced the normal version of the HTT protein but this did not lead to any psychiatric or cognitive behavioral deficits, although it could result in motor abnormalities.

“These studies examine for the first time the tolerability and efficacy of non-selective human HTT lowering and demonstrate the approach is well-tolerated, even in the absence of background wild-type [normal] huntingtin protein,” Van Deventer said.

In general, the treatment was well-tolerated by all animals, and did not affect their survival or body weight, or caused changes in brain activity and volume. Only the highest dose induced signs of astrogliosis, an abnormal increase in the number of astrocytes (star-shaped cells that support neurons) in response to the destruction of nerve cells, which indicates a potential “toxicity of this dose.”

“The impact on many features of Huntington’s disease with the AMT-130 gene therapy approach are encouraging and support its continued assessment in patients with this debilitating disease,” said study lead author Michael R. Hayden, Killiam professor of medical genetics at the Centre for Molecular Medicine and Therapeutics, University of British Columbia.

In a second study, “AAV5-miHTT lowers huntingtin mRNA and protein without off-target effects in patient- derived neuronal cultures and astrocytes,” published in the journal Molecular Therapy – Methods & Clinical Development, uniQure researchers and colleagues tested this gene therapy in neurons and astrocytes derived from induced-pluripotent stem cells (iPSC) from two patients carrying different HTT mutations.

Of note, iPSCs are fully matured cells that are reprogrammed back to a stem cell state, so that they are able to grow into any type of cell.

A single dose of AMT-130 lowered the levels of HTT by 68% in patient-derived neuronal cells. Moreover, additional analysis showed that the therapy had no effect on the activity of other genes, known as off-target effects, nor did it disturb the cell’s machinery responsible for processing microRNAs.

“These results are very encouraging in the context of AMT-130 as a potential gene therapy for Huntington’s disease, where durable and potent suppression of huntingtin protein is needed in the striatum and cortex,” Van Deventer said.