Rare neurological diseases: Setbacks for antisense molecules

An infant who received personalised RNA therapy for a genetic form of epilepsy died after developing hydrocephalus. The side effect has been reported in other treatments.

RNA-based therapies for KCNT1 epilepsy

In contrast to older gene therapies, which are designed to replace defective genes, the new approaches of antisense drugs consist of switching off the mutated gene by means of RNA and DNA snippets individually tailored to the patient, so that the cells cannot read the defective gene. An American research team produced the antisense molecule valeriasen, named after the patient. In September 2020, this was administered intrathecally to the girl for the first time.

Valeria initially had a lower seizure frequency under the experimental treatment, but died a year later, at the age of 3, after developing hydrocephalus. There is only one other child who also received the therapy. After an initial improvement, 2.5-year-old Lucy had the same side effect and almost died. Barely two months after initial injection, whimpering and strange movements of the limbs were observed, as if she was in pain. A short time later, every muscle in her body became rigid, her eyes twisted into whites and she screamed in pain. The drug was stopped, a shunt was put in and the girl survived.2

General questions arise about the approach

As the New York Times2 recently reported, more patients receiving ASO therapies for other rare diseases were experiencing hydrocephalus, and these cases may indicate a broader problem with the approach.1 "[The side effect on the brain] is a setback for this niche medical field, which has made rapid progress in the past five years," explained the NYT coverage.2

In 2016, the FDA approved the first antisense drug, nusinersen, for the treatment of spinal muscular atrophy. To date, several cases of hydrocephalus have also been reported in this population. In 2017, a research team made an antisense molecule specifically for six-year-old Mila, who suffered from a fatal form of Batten disease. They made the drug, called Milasen, in just 10 months - "far faster than the ten or more years it often takes to make conventional drugs". Before Milasen, no one had ever made a drug for a single person, let alone so quickly."2

In 2021, the manufacturer of AMT-130, an experimental antisense drug for Huntington's disease, announced that three out of fourteen patients in a clinical trial had also developed this severe side effect. The drug being tested worked with a virus that delivers DNA instructions designed to destroy the HTT transcript and thus lower HTT (for Huntington's disease).3

Hydrocephalus: not the only challenge of antisense drugs

Another programme, discontinued in 2022 due to negative study results, was aimed at developing an antisense drug for patients diagnosed with amyotrophic lateral sclerosis (ALS) and C9orf72 mutation (about 10% of those affected). There were no reports of hydrocephalus here, but the study programme was already discontinued after phase 1 because the cohort with the highest dosage of the experimental drug paradoxically had the most unfavourable course. Disease progression was faster here than in the placebo group.4 A similar fate befell the SOD1 antisense oligonucleotide tofersen, which failed to meet the primary endpoint in a first phase III study in ALS.5

There are also reports of setbacks in the development of antisense nucleotides outside neurology. Vupanorsen was considered a candidate for the treatment of dyslipidemia and fatty liver by selectively inhibiting ANGPTL3 biosynthesis in the liver. However, the programme was discontinued in 2022 after the TRANSLATE-TIMI-70 trial presented at the ACC Congress showed only a slight reduction in non-HDL cholesterol, but surprising side effects. Higher doses led, among other things, to increases in liver enzymes and fat accumulation in the liver - exactly the opposite of what was expected.6

Conclusions for medical practice

The hydrocephalus cases described above suggest that the problem could occur with many uses of such therapies, the NYT report concludes. What specifically causes the side effect to develop is currently being investigated.

Seth Greenblott, an attorney and business consultant, and Lucy's father (the second girl to receive Valeriasen), explained that "the worst part was wondering if we caused her more suffering. Did she have to endure any more than she already did? "Greenblott asked himself.

  1. Tailored genetic drug causes fatal brain swelling. https://www.science.org/content/article/tailored-genetic-drug-causes-fatal-brain-swelling.
  2. Hayden, E. C. Gene Treatment for Rare Epilepsy Causes Brain Side Effect in 2 Children. The New York Times (2022).
  3. In German only: Schwerwiegende Nebenwirkungen nach Behandlung mit Huntingtin-senkendem Medikament AMT-130, das sich derzeit in der klinischen Prüfung befindet. HDBuzz https://de.hdbuzz.net/329.
  4. In German only: Gaudlitz, M. Rückschlag in Therapiestudie gegen C9orf72-Mutationen. ALS-Ambulanz der Charitè https://als-charite.de/rueckschlag-in-therapiestudie-gegen-c9orf72-mutationen/ (2022).
  5. Mullard, A. ALS antisense drug falters in phase III. Nature Reviews Drug Discovery 20, 883–885 (2021).
  6. In German only: Rückschlag für Antisense-Medikament zur Lipidsenkung. Kardiologie.org https://www.kardiologie.org/acc-kongress-2022/lipidstoffwechselstoerungen/rueckschlag-fuer-antisense-medikament-zur-lipidsenkung/20279374 (2022).