02 Aug 2019

When participants in the Dominantly Inherited Alzheimer’s Network (DIAN) met in Los Angeles on July 13, they heard from their at-risk fellow travelers (see Part 1 of this series), learned how their tissue donations continue to advance AD genetics (Part 2), and got up to speed about how therapies based on that research are coming onto the scene. It’s not CRISPR quite yet, but RNA-based medicines, called ASOs, are in the clinic. Timothy Miller of Washington University, St. Louis, first told the audience of DIAN families, researchers, staff, and funders that other medical fields are increasingly looking to DIAN as a way to understand their own genetic forms of disease. Miller has developed gene-based therapies for ALS and frontotemporal dementia and, key to this audience, one that is in line to be tested by the DIAN trials unit (DIAN-TU) in the coming years.

Antisense oligonucleotides offer new hope for Alzheimer’s therapy.

An ASO silencing expression of tau is midway through a large Phase 1 trial.

CRISPR therapies a ways off for AD, but posting first successes in other indications.

Miller’s lab is devising drugs that consist of chemically modified, short nucleic acid sequences. Called antisense oligonucleotides, or ASOs, these drugs are designed to find a specific, matching RNA sequence inside of cells, and trigger their degradation (DeVos and Miller, 2013). This can turn down the expression of a troublesome gene, or turn up the expression of a needed gene. ASO therapies for the childhood diseases spinal muscular atrophy and Duchenne muscular dystrophy, as well as for a peripheral cardiomyopathy called transthyretin amyloidosis, are already FDA-approved (April 2019 news; May 2019 conference news). Investigational ASOs for Huntington’s disease and for ALS are in Phase 3 clinical trials.

In some cases, ASOs silence the mutant allele of a gene while allowing expression of the good copy. In other cases—and this is relevant to DIAN families—an ASO simply reduces the overall expression of a gene whose protein is part of the disease process. In this case that is MAPT, the gene for tau, the protein best known for the neurofibrillary tangles in AD. Miller’s group designed an ASO to bind to tau messenger RNA and intercept its translation, lowering the amount of tau protein in the brain. This approach appeared sensible because animal research suggested that lowering tau might benefit all cases of Alzheimer’s disease, familial and sporadic. By comparison, mutations in MAPT do not cause AD but rather frontotemporal dementia, and presenilins would require an ASO specific to each pathogenic mutation.

In mouse models of tauopathy, the tau ASO drug penetrated brain tissue and reversed neurofibrillary tangle pathology. The mice lived longer. “Our goal was to make these tauopathy mice stable, but the treatment did more. It made them better,” Miller told the audience (DeVos et al., 2017). In subsequent studies, the anti-tau ASOs reduced the amount of tau in the brains of non-human primates.

Miller partnered with Ionis Pharmaceuticals in Carlsbad, California, to develop the anti-tau ASO into an investigational drug. In 2018, Ionis partnered with Biogen to take its ASOs through clinical trials. Called Ionis-MAPTRx aka BIIB080, this drug is now in a Phase 1 clinical trial in 44 people with mild Alzheimer’s disease. The placebo-controlled study runs at 10 sites in Canada and Europe.

One site is at University College London, U.K. UCL researchers including Alison Goate, Nick Fox, and many others have cared for and studied people with familial dementias since the 1990s, and more recently built a unit to conduct innovative clinical trials for them. Called the Leonard Wolfson Experimental Neurology Center, it is expanding to be able to do more gene-based treatment studies, for example of ASOs. “The Wolfson center has changed our ability to do trials. It’s dedicated to conducting neurodegeneration trials early in the course of development. That is new. We have built a team and expertise in those studies,” its deputy director, Catherine Mummery, told the DIAN families in L.A.

Besides overseeing the tau ASO trial for Alzheimer’s disease at UCL, Mummery is already working with DIAN participants enrolled in DIAN-TU’s solanezumab and gantenerumab secondary prevention arms (Part 4 of this series). “Being part of DIAN-TU taught me what our patients go through when they are in DIAN. We learned that being patient-centered is very important. I try to apply that to other trials we do in sporadic AD,” Mummery said.

The tau ASO trial is about midway through. “The first person was dosed in our unit in November 2017. It was nerve-wracking for her, and for us, but it went well. We have done 16 doses of this drug at our unit, all without serious adverse events. We learn a lot about how to conduct these types of trial so that they are not so burdensome, and so that we give the medication in a comfortable way,” Mummery said.

The trial follows a multiple-ascending-dose format, where scientists give increasing doses to four cohorts of people, and wait between cohorts to see if the prior dose was safe. The trial’s first and second cohorts are complete, and the third cohort nearly so. Participants are being watched for potential on-target effects that would indicate that lowering tau is detrimental, for off-target effects that would indicate the ASO silences RNAs other than tau’s, and for side effects indicating the ASO activates the immune system in untoward ways. “These trials require a lot of safety monitoring. We are very cautious,” Mummery said.

Results are expected next year, both on safety and on whether the ASO lowered tau levels in the participants’ CSF. Determining whether lower CSF tau stops or slows the disease and its symptoms will require a Phase 2 trial, in which people are treated for longer than the three months the ASO is given in the current Phase 1 study, Frank Bennett of Ionis told the audience in L.A. A competitor of Ionis, Wave Life Sciences, is also starting to make ASOs against target RNAs in Alzheimer’s disease; this company dispatched a staff neurologist, Serena Hung, to the DIAD family conference. One idea for additional ASO therapies in AD is to silence expression of the APP gene.

Because ASOs do not cross the blood-brain barrier, both Ionis and Wave Life are currently delivering theirs intrathecally, in other words, by way of an injection into the spinal canal. The anti-tau ASO trial offers an open-label extension, at which point investigators see how much participants mind this invasive form of drug delivery. “Every person chose to continue to open-label; that tells us a lot about how tolerable this is,” Mummery said. Even so, she would like to transition to less-onerous delivery modes, for example using little pumps implanted under the skin.

The goal of delivering ASO therapies in a way that enables them to cross the blood-brain barrier is an active area of study. “It’s a challenging problem that we have not solved yet,” Bennett told the families. But even though intrathecal injection is cumbersome, Miller insisted that people tolerate it well in ALS, Huntington’s, and other ASO indications. “Our goal is to develop drugs that have a major effect and are therefore worth delivering in this way,” he said.

This ASO is but one of a handful of drugs the DIAN-TU drug selection committee are currently evaluating for a series of tau-based biomarker trials they intend to run beginning in 2020. The goal, said Randy Bateman of WashU, is to have sufficiently well-understood amyloid- and tau-based therapies in hand for combination trials.

And what about CRISPR? Two years ago at the DIAD family conference, a young woman stood up and asked when CRISPR therapies would repair her family’s mutation directly in their DNA. “CRISPR is a fantastic idea, but not quite ready for human trials in Alzheimer’s disease,” Miller said in L.A. Research on it is happening. For example, WashU’s Celeste Karch is using CRISPR to repair the mutations in neurons cultured from induced pluripotent stem cells (iPSCs), which she derived from DIAN participants’ fibroblasts. The DIAN genetics core has banked some 100 fibroblast lines spanning 34 APP and presenilin mutations as a resource for CRISPR studies, among others. These lines were made possible by skin biopsies donated by DIAN family members, and they are available to other labs for study.

But that is just a start. Scientists still need to work out how to ensure the CRISPR repair mechanism cuts DNA only at the site of the pathogenic mutation. They also need to figure out how to get a sufficient amount into the brain, and show that irreversibly editing the DNA in a person’s brain cells is safe.

Even so, CRISPR therapy is making progress on diseases that are considered lower-hanging fruit, in part because their targets are easier to reach, such as the blood or the eye. The first human success story came out this week, in a woman with sickle-cell anemia (see NPR story). For this therapy, the women’s blood cells were treated with CRISPR outside her body, and reinfused. On July 31, the first in vivo CRISPR therapy—in which the gene editing happens inside the patient—started enrolling for its first clinical trial. This investigational medicine is injected into the eyes of children, in hopes it will repair a mutation in the CEP290 gene in their retina that leads to blindness. For an update on DIAN clinical trials, see Part 4.—Gabrielle Strobel