This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

Amyloidosis Conferences



What is the potential of antisense drugs for rare neurological disease?

Take-home messages
  • ASOs can be used as drugs to change the function or stability of a target RNA
  • Intrathecal dosing of ASOs allows them to reach target RNA within brain cells
  • Many ASOs have been approved in the treatment of neurological diseases and others are in development

Dr Frank Bennett, Chief Scientific Director at Ionis, spoke to the virtual delegates of the 7th Congress of the European Academy of Neurology (EAN) – Virtual 2021 and 2021 Peripheral Nerve Society (PNS) Annual Meeting, sharing his views and current data for the use of antisense drugs for rare neurological diseases.

What are antisense oligonucleotide (ASO) drugs?

ASO drugs are synthetic oligonucleotides designed to bind to RNA through complementary base-pairing. Once bound, they can carry out a variety of functions, depending on factors such as binding location and chemical modifications within the oligonucleotide, to modulate the stability or function of the RNA.

The two most common mechanisms of ASOs, RNase H1-dependent degradation and RNA interference (RNAi), promote selective degradation of the target RNA. RNase H1-dependent degradation uses an ASO containing DNA to recruit RNase H1, an enzyme that recognises and degrades RNA-DNA duplexes, whilst RNAi uses the Ago-2 enzyme to promote RNA degradation. ASOs can also be used to modulate RNA processing such as splicing, to promote skipping or inclusion of exons, or translation, to inhibit or promote the production of proteins from the target RNA.

What are the benefits of ASO drugs?

  • They are a direct translation of genomic information to a drug; if you know the sequence of a gene of interest, you can design an ASO to target it
  • They are targetable to any RNA within the body, eg coding or non-coding RNA, microRNAs, etc
  • They have an efficient drug discovery process meaning they can be designed to treat individual patients
  • Their effects are titratable and reversible; this is in contrast to gene therapy which has more permanent effects

ASO drugs are widely used, with 12 drugs approved (largely for the treatment of rare diseases) and >50 in clinical trial.

How do ASOs function in the brain?

With systemic dosing, ASOs are not expected to cross the blood-brain barrier. To overcome this, they can be injected into the cerebrospinal fluid by lumbar puncture into the intrathecal (IT) space. This method of delivery has been used for >11,000 patients, with diseases including Huntington's disease, spinal muscular atrophy and Parkinson’s disease, and results in rapid and broad distribution of the drug throughout the neural axis and into brain tissue.

Dr Bennett shared results from rats to demonstrate the targeting and effects of ASOs in the brain. Imaging showed distribution of ASO from the base of the spine into the brain within 15 minutes of IT dosing, and immunohistochemistry confirmed the delivery of ASO to brain cells. Dual fluorescence in situ hybridisation was used to assess the effects of ASO in various cell types within the brain (neurons, oligodendrocytes, microglia and astrocytes). This showed fairly consistent suppression of a target RNA (Malat1), with oligodendrocytes being slightly more sensitive to the ASOs than the other cell populations.

Further evidence of the effects of ASO on target mRNA in the brain came from non-human primates. Substantial knockdown of Malat1 expression was observed in the spinal cord and brain regions such as the cortex and hippocampus. Deeper brain regions demonstrated some knockdown in expression, but this was somewhat reduced versus the more superficial regions.

Ongoing clinical trials with ASOs

Many ASO drugs are in clinical development, or late-stage discovery, for a broad range of neurological diseases.

Presenting at the PNS meeting, Dr Bennett discussed hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, a rare disease for which the ASO inotersen is already approved. Ongoing research, aiming to improve on the profile of inotersen, includes a clinical trial for a LICA-conjugated antisense drug called eplontersen that targets the hepatic production of transthyretin (TTR). Eplontersen is highly potent and has a longer duration of effect than inotersen, meaning that it can be administered in lower doses (improving tolerability) and less frequently (improving convenience). In phase I trials, a robust (>90%) reduction of TTR has been observed, with a favourable safety and tolerability profile. The phase III NEURO-TTRansform study is now underway to compare eplontersen and inotersen in patients with hATTR amyloidosis with polyneuropathy.

At the EAN congress, Dr Bennett instead focused on the progress that has been made with ASOs for the treatment of amyotrophic lateral sclerosis (ALS).

Around 15% of ALS cases are caused by known gene mutations, including SOD1, C9orf72 and FUS, which can be targeted by ASOs:

  • Tofersen, designed to target SOD1, demonstrated significant reductions in the concentrations of SOD1, and the disease biomarker neurofilament light chain, within the cerebrospinal fluid in phase I/II studies, as well as slowing of the decline of patient function over 3 months. A phase III study is due to be completed this year
  • A phase I/II study is ongoing for an ASO targeting C9orf72
  • Toxic gain-of-function mutations in FUS are the most common inherited cause of ALS (25%). Mutant FUS aggregates in the cytoplasm and causes motor neuron degeneration. An expanded access program for an ASO targeting FUS was initiated in 2019 and has enrolled and treated a number of patients. A pivotal, phase III, placebo-controlled study aiming for approval of this drug has been initiated this year

85% of ALS cases are sporadic however, and Dr Bennett shared that these too can be targeted by ASOs. "Not ignoring the sporadic population out there, we've been working with Biogen to identify an antisense drug that targets Atxn2, based on very elegant basic research studies, such as it might be useful to treat all forms of ALS." This ASO is currently in phase I/II clinical trial.

The approval process for drugs is not always an easy one though, even if pre-trial results look positive. A phase III trial for tominersen, a huntingtin-lowering ASO, was stopped early based on a risk-benefit analysis, although no new safety concerns were raised. Small patient numbers can also impede the robustness of clinical trial data; in discussing the phase III FUS-ALS trial, Dr Bennett hoped the data will be strong enough. "The incidence of ALS is so low that enrolment of patients and capturing them early enough in their disease will be somewhat challenging."

Dr Bennett concluded his presentations with an overview of the key attributes ASOs have for addressing challenging neurological diseases. They can be broadly distributed throughout the spinal cord and deep into brain structures, they have high specificity for targeting individual gene variants and can be designed to target currently 'undruggable' targets, and they can be designed to exact a variety of mechanisms.

Based on: Bennett F. Antisense drugs for rare neurological diseases. Presented at the 7th Congress of the European Academy of Neurology (EAN) – Virtual 2021, 19-22 June 2021; Bennett F. Antisense drugs for rare neurological diseases. Presented at 2021 Peripheral Nerve Society (PNS) Annual Meeting, 12-13 and 25-27 June 2021

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