ARBUTUS - EXHIBIT 2018
`Moderna Therapeutics, Inc. v. Arbutus Biopharma Corporation - IPR2019-00554
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`(ref. 4). Meanwhile. other researchers have
`shown that. in cultures of human cells. RNAI
`can similarly combat viruses as diverse as
`respiratory syncitial virusfi. and those that
`cause influenza“ and polio7.
`RNAi may work like a charm in petri
`dishes — but what about in live animals?
`
`Mark Kaye geneticist at Stanford University
`in California, addressed this question by
`fusing a genetic sequence from the hepatitis
`C virus to a gene for the enzyme luciferase.
`which stimulates a reaction that emits light.
`When Kay injected the fused gene into
`mouse livers, he could track its location by
`detecting the glow. And when the mice were
`treated with siRNAs targeted against
`the
`hepatitis C gene. this glow dimmed dramati-
`cally“. Hepatitis C doesn't make mice sick.
`but Kayand his colleagues have since gone on
`to show that RNAi can drastically reduce
`signs of infection by hepatitis B (ref. 9).
`which can damage the animals' livers.
`
`Firm plans
`Results such as these are attracting intense
`commercial
`interest.
`In August. Kay
`announced that he has licensed his work
`
`on hepatitis C to a company called Avocel
`in Sunnyvale. California. which aims to
`develop RNAi therapies against the disease.
`Other RNA pioneers are lining up with
`their own start-up biotech firms. For
`instance. Phillip Sharp of the Massachusetts
`Institute of Technology in Cambridge. who
`shared the Nobel Prize in Physiology or
`
`Combating the incurable: researchers are testing
`the Idea that the. RNAI pathway. which shuts
`down the genes of invading viruses. can block
`the replication of hepatitis C virus (far left. RNA
`shown in yellow) and HIV (left and middle left).
`
`company merged with
`this
`June,
`In
`Ribopharma of Kulmbach in Germany.
`Both Avocel and Alnylam are planning to
`begin clinical trials as early as 2005. Anti hot
`on their heels is Sirna Therapeutics of Bottl-
`der. Colorado, which has already raised
`US$43 million from investors. Sirna aims to
`
`develop therapies for hepatitis C and an eye
`condition called macular degeneration. For
`now. these Companies are maintaining ami-
`cable rclations. But the situation could gel
`messier as RNAi moves towards the clinic.
`beaauso patent offices around the world have
`not yet decided who owns the rights to some
`kity RNAi -based technologists.
`Before worrying about the ownership of
`key intellectual property. however. scientists
`must figure out how to make RNAi therapies
`workffhey are facing some formidable tech-
`nical barriers. chief among which is
`the
`problem of getting siRNAs into the right
`cells. This is not a trivial issue. because RNA
`is rapidly broken down in the bloodstream.
`and our cells don't readily absorb it through
`their membranes. And even when RNA gets
`into its target cell . scavenger proteins quickly
`chew it up. "The major hurdle right now is
`delivery. delivery. delivery." says Sharp.
`Researchers are exploring a variety of ways
`to cotnbat the problem. Some Involve tech-
`niques developed to facilitate an older tech-
`nology known as ‘antisense'. The idea behind
`antisense is to muffle a cell's single-stranded
`mRNA — the 'sense' strand — using a piece of
`antisense RNA with a 'complementary~
`
`news feature
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`
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`sequence that binds tightly to the mRNA.
`This. the theory goes. should prevent
`the
`mRNA from being translated into protein.
`Scientists tried a variety ofways to get the anti-
`sense RNAs into cells — for example. they
`packed the RNA inside fatty globules. called
`liposomes. which can cross cell membranes.
`But antisense has not performed well in clini—
`cal trials. partly because these delivery systems
`were not particularly effective. Khvorova
`believes that the medical benefits of RNAi will
`be huge if the delivery issues can be resolved.
`" But we've looked ata lot of the delivery meth—
`ods that have been used for antisense. and so
`
`far I haven't been impressed." she shys.
`
`Harmless HIV
`Another option is to use a harmless virus as a
`vector to ferry RNAi-triggerlng genes into
`their target cells. Molecular biologist John
`Rossi of the Beckman Research Institute of
`
`the City of Hope Medical Center in Duarifi.
`California. is experimenting with one such
`vector, based on a version of HIV from
`which the disease-causing genes have been
`stripped. Together with (inlleagurm led by
`Ramesh Akkina of Colorado State University
`in Fort Collins, RLJSSi engineered this vector
`to contain sequences encoding siRNAs tar-
`geted against HIV genes. The researchers
`used their vector to infect the human stem
`
`cells that develop into immune cells. Next.
`they either grew the cells. into mature cells in
`the lab. or injected them into mice from a
`special Strain that accepts human trans-
`plants. in both cases. the mature immune
`cells fought off HIV when researchers tried
`to infect them with disease-causing HIV in
`culture dishes”.
`Rossi hopes that a similar technique could
`work in human patients with HIV. Doctors
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`news feature
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`would extract stem cells from a patient's bone
`marrow. infect them with the RNAi—triggern
`ing vector. and then put them back into the
`patient. Rossi is now working to perfect this
`technique in mice. and is also beginning tests
`in rhesus monkeys to ensure that the treat-
`ment has no unwanted side effects. He hopes
`to convince the US Food and Drug Adminis-
`tration to authorize a clinical trial in the next
`two or three years. "i think when wegetail this
`data compiled we'll have a fairly free road into
`a stem—cell trial." Rossi predicts.
`This may be so, but there are nagging
`safety concerns about vectors made from
`viruses in the same family as HIV, which are
`called retrovirusesThis is due to the fact that
`retroviruses work by forcing their way into a
`cell's own DNA. If the vector lands in the
`wrong place it can damage important genes
`and even cause cancer. These concerns were
`
`borne out by last year's revelation that a
`retroviral vector had triggered leukaemia in
`some Children in a gene-therapy trial“.
`Because of these concerns. Rossi says that he
`will not use stem cells in his first clinical trial.
`
`treat mature
`initially
`instead. he will
`immune cells. because these cells are less
`likely to grow outofcontrol.
`
`Safe delivery
`Kay. meanwhile. is pinning his hopes for an
`RNAi vector on a virus known as adeno—
`
`associated virus. or AAV. He has already used
`AAV-based vectors in clinical trials of gene
`therapy against haemophilia”. AAV does not
`cause disease in people. and so far there has
`been no cause for any serious safety concern
`— even though AAV can also integrate into
`a cell's own DNA.
`
`Another important question mark hang-
`ing over RNAi is its specificity. Before regula—
`tors give the go—ahead for a clinical trial.
`scientists need to prove that that RNAi will
`not shut down vital human genes as well as
`the target viral sequences.
`Some studies on specificity have yielded
`encouraging results. in May this year. for
`instance. researchers led by Patrick Brown of
`Stanford University reported on experi~
`ments in which they engineered human kid-
`ney cells to produce a fluorescent protein.
`They shut down the gene for this glowing
`protein by using RNAi. and then used DNA
`microarrays to monitor some 20.000 other
`genes — none ofwhichseemed to be affected
`by the treatment”.
`Butjust a couple of weeks later. researchers
`with Rosetta lnpharmatics in Kirkland,Wash—
`ington, cast a shadow over this rosy picture.
`The Rosetta team. led by Aimee Jackson and
`Steven Bartz. used a range of different siRNAs
`to target two genes in cultured human cells.
`Disturbingly. the treatment caused changes in
`the expression of dozens of other genes.
`
`
`
`Little helpers: Mark Kay hopes to use harmless
`viruses to deliver RNAi therapy to patients.
`
`Jackson and Berta are not sure why their
`results were so different from those obtained
`
`by Brown's team. but one possible explana—
`tion is that they used larger doses of siRNA.
`The Rosetta researchers also tested for off-tar-
`
`geteffectssoonerafterbeginningtheirexperb
`mcnt than other groups have in their studies.
`But whatever the explanation. the findings
`have shaken up the RNAi camp. "We've had
`some really lively discussions." says Barta.
`New data from a group at Case Western
`Reserve University in Cleveland. Ohio. seem
`to support the Rosetta findings”, Last week.
`Bryan Williams and his colleagues reported
`that when they introduced siRNAs into cells,
`certain genes that are part of the interferon
`
`
`
`system were activated. a mechanism by which
`cells shut themselves down in response to
`invading germs. The siRNAs activated genes
`that act early in the interferon pathway. and
`Williams’group did not measure whether the
`activated genes stopped working. But the
`team says that its findings provide a warning
`that off-target effects are perhaps more com—
`mon than scientists have realized.
`
`Researchers argue that these hints of offs
`target RNAi effects highlight the need for a
`deeper understanding of how.exactly. the sys-
`tem works. For instance. we still don't know
`for sure how many proteins work together to
`shut down a target mRNA. it's also unclear
`why sortie siRNAs are incredibly effective.
`whereas others. targeted at a different region
`of the same gene. don't work as well. Given
`these unknowns. some researchers urge cau-
`tion before rushing into clinical trials. ”Before
`you know what you could perturb. you have
`to know what‘s there." says Tom Tuschi, a
`biochemist and RNAi pioneer at Rockefeller
`University in New York.
`Even some of the scientists working in the
`commercial sector. where excitement about
`
`is most
`the clinical prospects of RNAi
`intense. agree that a great deal of ground-
`work remains to be clone. " For real clinical
`development. this has to be done right." says
`Khvorova. "Investing a little more time on
`the basic steps will pay back in years of time
`savedlater on."
`
`But despite all of these caveats. most
`researchers working in this fast-moving field
`have high hopes that RNAi will deliver on its
`therapeutic promise. ”This is the honey-
`moon period; things are looking great," says
`Kay. "We will encounter technological issues
`along the way. but our goal is to solve these
`problems and get it to work."
`I
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`entrained-In.
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`Williams. B R. G i’VarunI Cit-113ml del'll'i lfllflinchlfliifi E2003)
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`Sirna Therapeutics
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