In recent years, two antisense oligonucleotide therapies have hit the market, at least nine more are in clinical trials for the treatment of neurologic diseases, and nearly two dozen are in preclinical testing, including ASOs for Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, frontotemporal dementia, spinocerebellar ataxias, pain, and rare disorders. At the 70th annual meeting of the American Academy of Neurology, April 21 to 27 in Los Angeles, researchers reported on Phase 3 data and open-label extensions for treatment of spinocerebellar ataxia and familial amyloid polyneuropathy (see Part 1 of this story) and on the latest data in their efforts to develop therapeutic ASOs for suppressing expression of huntingtin, tau, and C9ORF72 transcripts.

  • ASOs to treat Alzheimer’s, Huntington’s, Parkinson’s, ALS, and some rare neurological disorders are in development.
  • A clinical trial to test a tau ASO in people with mild AD has started.
  • Scientists expect to start testing a C9ORF72 ASO in ALS by the end of the year.

“Antisense oligonucleotides are bringing a new wave of enthusiasm and excitement to the field of neurologic diseases,” said John Day of Stanford University.

Until recently, researchers doubted it was feasible to get enough ASOs across the blood-brain barrier and distributed across the human cortex, or subcortical regions, for them to effect a therapeutic benefit. However, evidence has been accumulating that this problem is surmountable. For example, at AAN, Frank Bennett from Ionis Pharmaceuticals in Carlsbad, California, showed that after injecting an ASO against mRNA for the transcription factor MALAT1 into the CSF of nonhuman primates, levels of the target RNA dropped in every one of more than 30 different brain regions analyzed. Reductions ranged from 20 percent in deep areas, such as the putamen and globus pallidus, to more than 90 percent in the spinal cord and several areas of the cerebral and cerebellar cortices. MALAT1 expression in most brain regions fell to or below half. Bennett noted that increasing the potency of the ASO knocked down MALAT1 transcripts more efficiently in deep brain structures. Similarly, in an online presentation last month, Michael Ehlers of Biogen, Cambridge, Massachusetts, claimed that in a nonhuman primate, an intrathecal bolus of an anti-α-synuclein ASO robustly lowered both α-synuclein mRNA and protein, not only in temporal and dorsal prefrontal cortices, but in the substantia nigra, an important target for Parkinson’s treatment.

In the Clinic. Some antisense drugs for neurological diseases are approved, others are in clinical trials. [Courtesy of Frank Bennett, Ionis Pharmaceuticals.]

At AAN, Sarah Tabrizi, University College London, summarized data from a Phase 1/2a trial of the anti-huntingtin ASO IONIS-HTTRx. Last March at the CHDI Huntington’s disease conference, Tabrizi reported that the treatment lowered mutant huntingtin in the CSF by 40–60 percent during the 13-week trial (Mar 2018 news). In Los Angeles, she added data from the follow-up period when participants were off the drug. She said that four months after treatment had ended, participants in the treatment group scored no better than those on placebo in the UHDRS, a composite scale of HD severity based on measures of motor, cognitive, and behavioral health. “We don’t expect clinical change over seven months in a study with a relatively small number of patients in stage 1 HD,” Tabrizi said.

In post hoc analysis, the researchers did find some associations between reduction in mutant huntingtin in CSF, improved scores on the UHDRS, and individual components of the composite at day 85, the last day of dosing. However, no correlation was found with the Stroop test, a measure of attention and mental flexibility, nor with total functional capacity, an indicator of a person’s ability to live independently. “These findings are post hoc and exploratory; they require replication and extension in a longer and larger study,” cautioned Tabrizi.

Ionis’ Laurence Mignon described a clinical trial to test IONIS-MAPTRx, an ASO that destroys tau pre-mRNA. This ASO recruits RNAse H to exon 9 of the tau transcript. The primary goal of the trial is to assess safety and tolerability in patients with mild AD, but it will also examine CSF pharmacokinetics as a secondary endpoint, as well as biomarkers and clinical outcomes as exploratory measures. Completing the first part of a plan to test multiple ascending doses, a group of eight patients, aged 50–75 years, recently received the last of four intrathecal injections of the ASO, with the second group just getting started, said Mignon. The researchers expect to test four cohorts, totaling 44 patients. Tim Miller and colleagues at Washington University, St. Louis, had previously reported that the first-generation tau ASO, TauASO-12, prevented and even reversed tau pathology when injected into the spinal fluid of transgenic mice expressing the human tau gene. The ASO also normalized nest-building behavior, and lengthened lifespan (Jan 2017 news). In Los Angeles, Mignon also pointed to studies indicating that cell and animal models tolerated tau reduction well, especially in adulthood. Moreover, intrathecal injections of IONIS-MAPTRx in cynomolgus monkeys knocked down tau mRNA by more than half in the spinal cord, frontal cortex, and hippocampus, she said.  

Robert Brown, University of Massachusetts in Worcester, expects to move ASOs targeting RNAs implicated in ALS into the clinic by the end of the year. The most common genetic cause of familial ALS and frontotemporal dementia (FTD) is a large G4C2 hexanucleotide repeat expansion in the first intron of the C9ORF72 gene. Wave Life Sciences, an oligonucleotide therapies company based Cambridge, Massachusetts, has created the ASO WVE-3972-01 to silence the expanded allele. Unlike other ASOs, which are made as a mixture of stereoisomers, WVE-3972-01 is stereochemically pure. Although all molecules of a given ASO share the same nucleotide sequence, stereoisomers differ in the three-dimensional orientation of atoms around some of their bonds. This means the isomer with the most therapeutically useful configuration can get diluted by others in the mix whose shape is suboptimal. By controlling the geometry of the ASO backbone during synthesis, Wave Life Sciences produces uniform oligonucleotides that can be selected for better RNAse H targeting and resistance to degradation by single-strand nucleases (Iwamoto et al., 2017). Brown reported that in head-to-head comparisons, stereopure ASOs were more selective and more potent than regular ASOs with mixed backbone configurations.

So what about WVE-3972-01? When injected into the cerebral ventricles of mice expressing the human C9 gene with a repeat expansion, the ASO found its way into the cortex and spinal cord, and was still detected eight weeks later in the nuclei of spinal cord motor neurons. At that time, levels of toxic poly-glycine-proline (GP) peptides encoded by the mutant C9 gene dropped by more than 80 percent and toxic RNA foci were cut roughly in half, while total C9 mRNA and protein levels fell only slightly. Brown said his group is now putting WVE-3972-01 through toxicology tests.

In response to an audience question, Brown acknowledged that C9 produces sense and antisense mRNA transcripts that both encode toxic poly-dipeptides; however, WVE-3972-01 only targets the sense transcript. “For me, the $64,000 question is: Are we going to have to reduce both strands?” he said. Brown’s data suggest that at least polyGP, which can also be made from the antisense strand, is robustly lowered by an ASO that targets only the sense strand. However, this ASO leaves the proline-arginine dipeptide, encoded by the antisense strand, unchanged.

Lindsey Hayes of Johns Hopkins University in Baltimore showed data hinting that targeting either one of the strands alone may be enough to combat at least some aspects of ALS pathology. Using induced pluripotent stem cells derived from C9 patients, Hayes found that treating the cells with ASOs against either of the two strands restored nuclear pore proteins and Ran, a nuclear protein required for nucleocytoplasmic transport, to their normal locations within cells. “Surprisingly, both [ASOs] independently rescue these pathologies,” said Hayes. “In vitro, dual therapy does not appear to be required to rescue nuclear transport.”

What Next?
On April 20, Biogen announced a $1 billion deal with Ionis to develop ASOs to treat neurologic diseases, including AD, PD, ALS, FTD, and progressive supranuclear palsy. Both companies hope to replicate the success of nusinersen. Ionis will handle early stages of target validation, Biogen will take over development from toxicology to commercialization. In an investor presentation, Biogen’s Ehlers said he expects to have up to seven candidates in the clinic within two years and to validate 50 targets in the next decade.  BIIB5Rx, IONIS-BIIB6Rx, and IONIS-BIIB7Rx are in preclinical development for undisclosed neurodegenerative diseases. “We think ASOs are the most advanced genetically based approach for targeting neurological diseases,” said Ehlers, adding he expects ASO validation and production to be faster than for small molecules.

Scientists at AAN also discussed other gene therapies (see Part 1 of this story). Receiving intrathecal doses of an expensive ASO drug for life has obvious disadvantages, but it avoids irreversible changes that might come with permanently modifying genes and potentially harmful immune reactions elicited by some gene delivery vectors. Ehlers considers ASO and gene therapy complementary and said Biogen is exploring combination approaches. Others worried that combining ASO drugs with gene therapy would raise enormous price tags even further. Nusinersen, the ASO approved for treating spinal muscular atrophy, at present costs $750,000 for the first year of treatment and $375,000 each year thereafter.—Marina Chicurel


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News Citations

  1. As RNA Therapies Come of Age, Efficacy Remains Weak
  2. Antisense Therapy Cuts Huntingtin Protein in CSF by Half
  3. Antisense Oligos Tango with Tau Transcripts to Reverse Tauopathy

Therapeutics Citations

  1. BIIB080

Paper Citations

  1. . Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017 Sep;35(9):845-851. Epub 2017 Aug 21 PubMed.

Further Reading