Gene therapy for Huntington’s: great highs, deep lows

At the end of September, the share price of biotech company uniQure turned somersaults four times in a single day. That explosion in the share price followed a press release from the company and a BBC news article headlined ‘Huntington’s disease successfully treated for first time’. All of this arose from a clinical study using gene therapy against Huntington’s disease, a hereditary and fatal condition that resembles a combination of Alzheimer’s, Parkinson’s and ALS.

Eric Reits, Professor of Cellular Imaging (AMC-UvA) and Huntington’s researcher, would have liked to have been prepared for the news. Instead, his inbox and messaging apps suddenly overflowed with questions. ‘The news went through families like a shockwave.’ He usually hears about the latest developments among the first to know. ‘I think uniQure had to prevent insider trading.’ In his research, Reits always works closely with the Huntington’s patient association. He is also an adviser to the Huntington Campaign Team. ‘We put together our own statement as quickly as possible to inform them in a nuanced but hopeful way. The BBC had phrased the news somewhat optimistically. This is not yet a cure. But it does offer hope, certainly given what else is still in the pipeline.’

CAG-CAG-CAG

The cause of Huntington’s lies in a mutation in the gene for the protein huntingtin (Htt), which is found predominantly in the brain. Without this protein, nerve cells do not function properly. Htt contains a repeat of at least six copies of the amino acid glutamine. This is due to a so-called repeat sequence in the coding DNA (-CAG-CAG-CAG-…). People with Huntington’s have a repeat of more than 35–40 ‘CAGs’, and this causes instability in the gene.

‘The BBC had phrased the news somewhat optimistically’

Eric Reits, AMC-UvA

Over the course of a lifetime, the risk of the gene ‘going off the rails’ increases. In affected brain cells, ever longer repeats then emerge, leading to an ever longer glutamine chain in Htt. It also causes incomplete Htt; the protein then lacks a normal terminus. These fragments, laden with glutamines, clump together, and this damages brain cells.

The gene therapy developed by uniQure reduces the production of Htt. An adeno-associated virus (AAV) introduces DNA into brain cells that is the mirror image (antisense) of the beginning of the Htt gene. The ‘viral’ DNA is read and produces mRNA that is the mirror image of that of the Htt gene. The mirror-image mRNAs bind to one another, and because double-stranded mRNA does not naturally occur in cells, it is broken down. As a result, between a quarter and a half less Htt is produced.

Brain surgery

In the uniQure study, a phase I/II trial, thirty patients underwent the one-off gene therapy. Their health was then monitored for three years. During that time, they declined four times more slowly than expected, according to the biotech company. It is the first time a Huntington’s therapy has achieved such an effect. No serious side effects occurred either. The study is, however, limited in scope and focused primarily on safety and determining the correct dose.

Barely six weeks after the hopeful news came disappointment — for uniQure, but certainly also for Huntington’s families. In discussions about accelerated market approval, the American FDA indicated that it would not be approving the gene therapy for the time being. The stumbling block appears to be the choice of control group. Reits: ‘There was no genuine placebo group. The possibility that a placebo effect may be at play hits families hard.’

The absence of a placebo group stems from the fact that the gene therapy is administered during a ten-hour brain operation. A neurosurgeon injects the agent through a fine needle into the corpus striatum, the region deep in the brain that is most severely affected in Huntington’s. In Europe, a sham operation for a placebo group was not deemed ethical. In the United States, half of the study participants — depending on the draw — did undergo a ‘sham operation’; in their case, only an incision was made in the scalp. After a year, they were rolled into the study regardless. Because the health differences between patients and the ‘placebo group’ after the first year did not yield a statistically reliable result, uniQure opted for a comparison with a group of Huntington’s patients who had been monitored in the past. This was done in consultation with the FDA, but now proves insufficiently convincing. It means that more patients will first need to undergo the treatment in trials before market approval can be considered. Hard evidence will require the treatment of hundreds of patients in whom the slowing effect is sustained.

‘The news went through families like a shockwave’

Eric Reits, AMC-UvA

Spinal injection

In earlier studies, other companies and research groups attempted to administer antisense gene therapy against Huntington’s via an injection into the spinal cord. That is far less invasive. The idea is that the adenovirus finds its own way to the brain. However, in a Roche study, this strategy led to too many side effects. Nerve cells in the spinal cord suffer from a shortage of Htt because the therapy also takes effect there.

Research is now also under way into gene therapy that is selective for Htt with long repeats. This is achieved by targeting different parts of the Htt gene. Shorter, healthy variants of Htt can then continue to carry out their useful work. Such selective antisense gene therapy could then be administered via a spinal injection. The Leiden-based biotech company VICO, among others, is testing this method. A first study, likewise focused primarily on safety and establishing the correct dose, has been initiated.

Clearing the clumps

Reits is greatly encouraged by the ongoing gene therapy studies. ‘For the first time, there is hope of treatment.’ Ultimately, he expects patients to benefit most from a combination of therapies. Researchers are also making progress in preventing and clearing Htt clumps, though those therapeutic options have not yet reached the clinic.

These include specific proteins — chaperones — that counteract the clumping of Htt, and intrabodies against aggregates; these are antibodies that carry out their work inside the cell. Compounds are also being developed that tag clumping Htt so that the cell’s macrophages can clear it away. By using gene therapy to reduce the production of the overlong Htt protein and simultaneously clearing harmful clumps, the disease is being tackled on multiple fronts. Reits: ‘Because the dream is to prevent Huntington’s, not just slow it down.’