Antisense Therapies in Neurological Diseases

Jean-Baptiste Brunet de Courssou; Alexandra Durr; David Adams; Jean-Christophe Corvol; Louise-Laure Mariani


Brain. 2022;145(3):816-831. 

In This Article


The first successful strategy developed to treat SMN1-related spinal muscular atrophy opened the gate to antisense development and use in many neurodegenerative disorders. Some are very advanced or at the pre-approval stage such as in TTR-related hereditary amyloidosis, Duchenne muscular dystrophy, porphyria and amyotrophic lateral sclerosis. These successes also raise practical, ethical and clinical questions. Lifelong chronic iterative intrathecal administrations raise questions regarding logistical practical issues, but also regarding long-term tolerance. Applying previous successes to other disorders is not as simple as it seems, as shown by the recent failures in the field of Huntington's disease or due to long-term preclinical toxicity in multiple system atrophy and cystic fibrosis. The antisense therapeutic field is in its early emerging development and many unknowns remain. The exact mechanisms of these long-term deleterious effects are not perfectly known. This point will be of tremendous importance in the perspective of the new planned applications, for instance to other non-genetic degenerative disorders such as multiple system atrophy or Parkinson's disease, but also critical to premanifest mutation carriers, such as the SOD1 mutations carriers in the coming ATLAS trial (phase 3, NCT04856982) for amyotrophic lateral sclerosis.

From a care point of view, some children with intractable diseases will undergo lifelong treatment with unknown consequences on quality of life, depending on a treatment that is costly and not perfect (repeated intravenous or, even more so, intrathecal injections). For adults with milder disease forms—in spinal muscular atrophy, for instance—the cost–effectiveness balance will need to be assessed in the context of treatments with more modest effects as compared to their indications in lethal form.

For a more general application, and particularly in more common diseases such as Parkinson's or Alzheimer's diseases, administration routes will need improvement, as repeated intrathecal injections or neurosurgery cannot be applied on worldwide general scales. Recent treatment specifically targeting hepatocytes as in transthyretin-related hereditary amyloidosis led to a valuable simplification of drug administration—from intravenous to subcutaneous—and proved that targeted delivery to a cell subtype was feasible and efficient. Repeated intrathecal injections are more challenging and will hopefully be prevented by the development of new ways to bypass the blood–brain barrier. For instance, using ASO coupled with addressing proteins or opening the blood–brain barrier with ultrasound could prove to be useful. Furthermore, continuous expression of the desired ASO or siRNA by providing a potentially stable plasmid, coding for them, could provide a perspective of a way for single-dose treatments in non-dividing cells such as neurons. Target engagement in the CNS is often a challenge in the development of new therapeutic approaches in neurological and psychiatric disorders.

Treatment-related toxicity and adverse effects are still incompletely known and will require further knowledge acquired from ongoing developments. Dosing being stopped in recent trials involving ASOs in multiple system atrophy (NCT04165486) and Huntington's disease (NCT03761849) remind us that further understanding of the consequences of the antisense therapy are needed. Considerations such as doses of ASO potentially being too high and the consequences of widespread pathology in the brain, where the ASO can be deleterious, have to be taken into account. In the case of Huntington's disease, lowering both allele expression, or lowering the production of a normal protein in the case of multiple system atrophy, could have an impact on the normal functioning of the cells, because normal protein production is hampered by the treatment approach. Reports of neurofilament increase and ventricle enlargement in Huntington's disease patients treated with ASO are suggestive of these potentially deleterious consequences.[95,96] Specific allele targeting in Huntington's disease is an interesting lead to let the normal Huntingtin protein be produced, but may not be sufficient to prevent the deleterious effect related to Huntingtin protein dramatic drop. The recent failure of trials in Huntington's disease was disappointing to the whole community, in particular for the many participants and their families, but also the investigators. This could influence the dynamics of the next trials to come. As in every clinical trial, those innovative treatments need to be closely monitored as the consequences can be deleterious, if not harmful, such as the adverse events with inotersen in transthyretin-related hereditary amyloidosis. Glomerulonephritis and thrombopaenia that led to one death are now closely monitored. As this did not happen with patisiran, the nature of the antisense therapy could be involved in these specific adverse events. Another antisense therapy against cystic fibrosis was also recently halted, the inhaled Ionis-Enac-2.5-Rx. However, this setback has been stopped due to long-term preclinical toxicology results from a rat study showing unexpected lung inflammation, despite a positive phase 1 in healthy volunteers. This may not be directly linked to the same issue, probably different from the potential direct dose related toxicity in Huntington's disease, and was a timeline strategic choice from Ionis, but this highlights the need for long-term safety studies on gene therapy so the field can move forward safely. Even though the time is at the proof-of-concept stage with the first clinical successes, these global health-cost and quality-of-life considerations, and new insights on toxicity and/or lack of efficacy, will require further concerted reflections from the scientific and healthcare communities. The next developments and challenges of the field will be balanced between spreading this approach (i) to non-genetic common neurodegenerative disorders; (ii) to premanifest mutation carriers in genetic disorders, while competent authorities may ask for longer toxicology studies before clinical trials start, and some industrials could be getting cold feet due to recent setbacks endangering the timelines of development that were planned, adding to recent patients' community disappointment; and (iii) to new more personalized approaches aiming at more specific ASOs development, either targeting more specifically the mutated allele or even managing to develop specific individual tailor-made ASOs in case of rare genetic disorders.