David Giljohann, PhD, CEO of Exicure, thought that he had made a mistake during his first year of graduate school when the controls he ran with his experiments gave some unexpected results. As he tells GEN, “a prepared mind favors following up on erroneous results.” Those data showed how well spherical nucleic acids (SNAs) go into cells on their own, and became the foundation of Exicure—a biotech company that is hoping to change the way nucleic acids are delivered into cells.

There was a lot of work being done in the mid-2000s, notes Giljohann, trying to formulate DNA or RNA into nanoparticles and use those to effect cellular entry. It was during his graduate work in the lab of Chad Mirkin, PhD, director of the International Institute for Nanotechnology and professor of chemistry at Northwestern University, as the first biologist in a chemistry lab (an experience Giljohann calls “an adventure”) that he started to work on SNAs, as delivery systems into cells.

SNAs consist of “densely packed synthetic nucleic acid sequences radially arranged on the surface of a nanoparticle.” Having the DNA or RNA on the outside of the particle is 180 degrees different from what had been done historically—with the nucleic acid encapsulated inside. According to Exicure, the SNAs spherical 3D architecture—which Giljohann refers to as a “kooshball” arrangement—gives the SNAs unique properties. SNAs are actively taken up by class A scavenger receptors which are widely expressed on cells. The SNA is endocytosed into the cells beyond just the liver without requiring transfection agents or chemical modifications that could cause side effects. And, they can be formed with almost any nucleic acid sequence including antisense, siRNA, miRNA, and aptamers.

It is a “compelling platform technology,” notes David Walt, PhD, faculty at Harvard Medical School, member of the Wyss Institute, and a scientific founder of Illumina and Quanterix, in addition to his board position at Exicure. For one, Walt tells GEN “it is, pretty much, 100% of the active agent.” Walt adds that other methods are often formulations with a small amount of nucleic acid in them. But, with SNAs, the nanomaterial is comprised exclusively of nucleic acid “with no ancillary molecules that could cause adverse effect or interferences.” That makes them “very modular” in that sequences can very quickly be changed to target a new indication. The polyvalency of the SNAs is another attribute that excites Walt. Meaning that, in a system that relies on DNA molecules binding to a particular sequence, in the event of dissociation, there are many other identical molecules present in a high density that can move right in and replace that molecule.

Walt’s connection with Exicure started when he met Mirkin, Exicure’s founder, “something like 25 years ago.” After they met at a conference in Spain, their close friendship has persisted. Walt is optimistic because, unlike many companies that have one molecule in the clinic that will have a binary readout—the drug either works or it doesn’t—Exicure’s platform technology can lead to multiple candidates in the clinic. They have, notes Walt, “derisked the possibility that any single readout will jeopardize the company because there are a lot of pots in the fire.”

David Giljohann, PhD, CEO, Exicure

“The challenge for the last 20 or 30 years has been how to get DNA or RNA to go into cells,” notes Giljohann. The first successes were in the liver because, when DNA and RNA is injected into the body, it normally gets picked up by the liver because it does not deliver well. In turn, people started going after liver based medicines first. Now, Giljohann tells GEN, “we can get our SNA into all types of cells and tissues outside of the liver” allowing them to get back into this “cool, fundamental idea of genetically targeted medicines.”

Robert Langer, ScD, institute professor in the department of chemical engineering at MIT shares the enthusiasm over SNAs, telling GEN that Exicure’s technology is “very exciting science that could enable new medical treatments.” He adds that all medical therapies “have huge developmental costs, clinical trial hurdles, regulatory hurdles, etc.” SNAs will be no different, asserts Langer, but, it will “be well worth it if these novel therapies can save and improve people’s lives.”

Exicure has three drugs in clinical trials at the moment; two in dermatology and one in oncology. Exicure wants to use SNAs to activate toll like receptor 9 (TLR9) in order to activate the immune response to advance cancer treatment. Once activated, the programmed immune cells go after the cancer systemically. TLR9 is the target of at least four other companies working in the immunotherapy space. One, Checkmate Pharmaceuticals, was founded by Art Krieg, MD. “SNAs activate TLR9 in a different way using different chemistries” notes Krieg. He adds that “there is different biology in the receptor depending on how it is activated.” The SNAs could be more effective in treating human disease. Or not. “We just don’t know yet,” notes Krieg.

In patients with mild-to-moderate chronic plaque psoriasis, an SNA drug called XCUR-17 targets an mRNA encoding interleukin 17 receptor alpha—a key protein that propagates inflammation. Exicure notes that they had five application sites per patient; three dose levels of SNA, a positive control, and a gel-only negative control (with no SNAs.) This allowed them to “show dose dependence, and eliminate variability because each patient served as their own control.” They note that 11 of the 21 patients treated with the highest strength XCUR17 gel had a reduction in redness and improvement in healing.

For the dermatology applications, Krieg is not sure how robust their penetration into the skin will be in humans since the skin exists as a barrier. Not only is getting the SNAs across the barrier of the skin and into the target cells in an efficient manner “a major challenge” but, Krieg recalls another historic problem in the antisense field. That is, the occurrence of biologic effects through mechanisms of action other than the RNAi. For example, he notes that the SNAs with the nucleic acids have a lot of negative charges. And, those negative charges could have effects, regardless of the nucleic acid target. “SNAs are early enough in their development that we still don’t know as much as we would like to know about what effects are due to the intended mechanisms of action and what other, unintended mechanisms of action might there be.”

Exicure is hoping to have a neurobiology program starting before the end of this year. Oligonucleotide therapeutics in the CNS is really taking off right now. “We know that exon skipping works,” notes Giljohann. But, he adds that patients are given huge amounts because the amount of drug that they are getting into the cells is very, very small. Because the SNAs have “100% cell transfection,” Giljohann asserts that all of the oligos are taken up which has a bunch of added benefits. The concentration can be less which is important for manufacturing, cost, and toxicity.

“In the early days, there was a lot of skepticism that the CNS was going to be an organ that could be treated with oligonucleotides,” notes Krieg. Krieg explains that oligonucleotides do not cross the blood-brain barrier and, although the intrathecal delivery was always a possibility, people were skeptical that it would work. But, Krieg notes that when the Nusinersen (Spinraza) data came out, illustrating the durable efficacy of Nusinersen in the CNS, with the additional positive results seen for Huntington’s disease, ALS, and others—a new wave of enthusiasm for oligonucleotide therapeutics in the CNS was created. “It’s early days,” adds Krieg. And, regarding the use of SNAs in the CNS, he notes that “their large size may actually work against them” as a larger molecule may not be able to diffuse as easily. But, he notes that, if the SNAs can give further improvements to the oligonucleotide therapy in the CNS treatments CNS, “that would be extremely interesting.”




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