By Clifton Leaf
January 4, 2018

Good morning. Yesterday, I wrote about two key trends that I believe will shape the healthcare industry in 2018 and beyond: self-aggregation and de-hospitalization.

Today, I offer a third prediction—this one in the realm of drug development: RNA-based therapies will shine as never before.

If 2017 was the year of DNA—a time of gene therapy breakthroughs and of the continued refinement of the gene editing tool CRISPR—then 2018, I foretell, will be the year of DNA’s kissing cousin: RNA, or ribonucleic acid.

Molecular biology’s famous “Central Dogma” states that DNA, the living computer code that makes up our genes, is first transcribed into RNA, which is then translated into specific proteins, which ultimately do the 24/7 work of the body and form its many structures. (There are some exceptions to the rule, as certain tumor viruses demonstrate—see the sad, heroic tale of Nobel laureate Howard Martin Temin, who had the effrontery to challenge said dogma.) But while single-stranded RNA has never shared top billing on the biological marquee with its elegant, gyring, double-stranded relative, it just might hold the answer to some remarkable cures. That’s because, in theory, thanks to that single wisp of intermediate code, the genes implicated in many diseases should be easier to quiet.

One way to shut down the communication link is through a snippet of RNA called “antisense”—which binds to the messenger RNA (a “sense”-making strip of nucleic acids) that is transcribed by a given stretch of DNA. In short, when antisense RNA matches up with and binds to messenger RNA (mRNA), or to a precursor strand called pre-mRNA, it stops the latter from conveying the instructions for making proteins. (There’s also a separate, related, strategy called RNA interference, or RNAi, which typically relies on one of two types of tiny RNA molecules—either small (or short) interfering RNA or microRNA—to silence genes. The journal Nature Reviews Genetics has a terrific animated video explainer here.)

The notion that antisense oligonucleotides might inhibit the progression of genetic diseases or tumor-causing viruses dates back to the late 1970s, when legendary molecular biologist Paul Zamecnik and colleague Mary Stephenson demonstrated the method’s viability against the Rous sarcoma virus. And it’s been one of those ideas that has excited—and taunted—researchers and drug developers ever since: one that, at the same time, is brilliantly intuitive and agonizingly hard to make work.

Though hailed as “a new therapeutic principle” in 1990, it nonetheless took another eight years for the FDA to approve the first antisense drug, fomivirsen—for the treatment of AIDS-related retinitis caused by human cytomegalovirus. The next antisense agent to earn approval didn’t get that nod until a decade and a half later, in 2013. That was for mipomersen, a medicine used to treat familial hypercholesterolemia, a hereditary condition that causes massive increases in LDL cholesterol. The hope was that antisense oligos for everything from cancer to HIV would roll off the pharmaceutical assembly line—but despite a generation of valiant effort, the successes on this front have been meager.

Now, it looks like the tide may at last be turning. In recent months, there have been promising results in RNA-targeting drugs for some rare neurological disorders.

And the reports from one early (Phase 1/2a) clinical trial of an antisense oligonucleotide called IONIS-HTTRx, made by California biotech Ionis Pharmaceuticals, suggest that this approach might one day stop Huntington’s disease—a cruel, progressive, and ultimately fatal neurodegenerative disorder. Huntington’s is caused by an inherited mutation in a gene called HTT, which encodes for a toxic protein that destroys brain neurons—damage that, over time, can severely limit a person’s ability to walk, talk, swallow, or even think clearly. As with functional genes, the aberrant Huntington’s gene sends its protein-coding instructions by way of a messenger: RNA. And in the recent randomized study—which was designed to assess the safety and tolerability of various doses in volunteers from Canada, Germany, and the UK—IONIS-HTTRx appeared to substantially block the gene’s pernicious message from getting through. The experimental drug, according to reports, sharply reduced the cell-killing protein in the subjects’ nervous systems and apparently had no major side effects. (The results have yet to be published.)

The gene-silencing strategy, in the form of RNA interference, has also showed promise against an uncommon neurodegenerative disease called hereditary ATTR amyloidosis, as Sy wrote about in Fortune’s year-end Investor’s Guide. Alnylam Pharmaceuticals, based in Cambridge, Mass., has so far spent 15 years developing patisiran, an investigational RNAi drug for hATTR—and this past November, at a scientific meeting in Europe, the company presented Phase 3 trial results that appeared to blow the research community away. The FDA, for its part, seems excited, too; shortly after the study presentation, it granted patisiran “Breakthrough Therapy Designation” status—a promise that the agency will expedite its review of the drug if and when it’s submitted for approval.

Today, there are a fair number of gene-silencing drugs in late-stage development and dozens of companies working in the space—and it feels like we could be close to a tipping point.

Human biology, of course, has a way of teasing and fooling those who try to solve its mysteries—so the latest upbeat findings may be yet another false harbinger of success. Nonetheless, I’d bet on this trend in 2018 and beyond. It just makes good antisense.

Clifton Leaf, Editor in Chief, FORTUNE


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