Upload
celia-henry
View
214
Download
1
Embed Size (px)
Citation preview
COVER STORY
DELIVERING RNA INTERFERENCE
Developing siRNA THERAPEUTICS depends on synthetic delivery systems CELIA HENRY ARNAUD, C&EN WASHINGTON
RNA INTERFERENCE is on the fast track. In the eight brief years since the RNAi gene-silencing mechanism was first uncovered, its discoverers have won the Nobel Prize and the first therapeutics based on it have entered clinical trials. The announcement just two weeks ago that Merck will acquire San Francisco-based Sirna Therapeutics, which is one of the major players in RNAi-based therapeutics, for $1.1 billion shows that big pharma is confident about the potential of RNAi therapeutics (C&EN, Nov. 6, page 11).
Therapeutics based on RNAi take advantage of this natural gene-silencing mechanism. They take the form of small, double-stranded RNA molecules just 19 to 21 nucleotides long—so-called small interfering RNAs, or siRNAs—which guide complementary messenger RNA to a protein complex known as RISC. RISC then
cleaves the mRNA and prevents its translation into protein.
In the first group of RNAi therapeutics, the siRNAs are administered directly to the disease location. For example, Sirna's lead candidate is directly injected into the eye to treat age-related macular degeneration, and Cambridge, Mass.-based Alnylam Pharmaceuticals' treatment for respiratory syncytial virus is delivered directly to the lung by inhalation. Sirna's candidate, which is being developed in partnership with Allergan, is in Phase II clinical trials, and Alnylam has recently launched the third Phase I clinical trial of its candidate.
"There are a number of diseases where local delivery would be all you need," says Judy Lieberman, a researcher at the CBR Institute for Biomedical Research at Harvard Medical School. But diseases that can be treated by such local administration are
ultimately limited, and "systemic delivery is still a problem," Lieberman says.
For RNAi to have the therapeutic impact that many people hope it will have, systemic delivery methods are needed. Such delivery systems are the focus of intense investigation by industrial and academic researchers.
Although nucleic acid therapeutics have been around in various forms for approximately three decades, they haven't yet been successful in the clinic, according to Barry Polisky, senior vice president of research and chief scientific officer at Sirna. "Nucleic acid therapeutics has really been an idea whose promise has not yet been realized," he says. "It's almost entirely due to the lack of attention paid to the delivery problem. It's hard to emphasize enough the central-ity of this issue."
The first examples of systemic delivery have been to the liver, for which multiple
WWW.CEN-0NLINE.ORG
TARGET Purple-and-green conjugates of peptides and double-stranded RNA target cell-surface receptors (purple) and deliver double-stranded RNA to the Dicer enzyme (orange), which cuts the RNA to the right size for RNA interference.
χ ο LU
(Λ <
16 NOVEMBER 13, 2006
"Isco Companion® is a fantastic time-saver for our discovery applications!' Andre Pearson, Cubist Pharmaceuticals, Inc.
"0 ur team at Cubist Pharmaceuticals is dedicated to developing new antimicrobials to combat the 'super
bugs/ We work up a lot of analogues looking for promising new leads.
Compared to HPLC for purification of isomers, the Isco flash chromatography system gives us equal purity and more than double the product recovery. The columns are so quick and simple to change that each of us sharing the system can use our own columns.
For me, the most useful features are the dual-wavelength detection, and the ability to change the gradient interactively to optimize separation on a key peak, or speed up the end of the run."
Discover how Teledyne Isco CombiFlash® systems can improve your purification. Call today or go to
www, isco.com/companion5.
DOBJBi A\~
looooooooo looooooooo looooooooo looooooooo looooooooo; loooooooooί Π00#00#000 BOOOOOOOOO -J, ,m. ,i ,j#tf,
"Color coding of the peaks and fractions makes it a piece of cake
to find the tubes I need. "
w TELEDYNE ISCO A Teledyne Technologies Company
Teledyne Isco, Inc. · 800.228.4373 · 402.464.0231 www.isco.com · [email protected]
REQUESTM0REATADINF0N0W.ORG
Speed · Performance · Reliability
COVER STORY
methods are proving feasible. Alnylam conjugated cholesterol to siRNA targeting the gene for apolipoprotein Β and showed that systemic administration in mice resulted in less production of the apoB protein in the liver (Nature 2004,43-2,173). Alnylam also reduced apoB in monkeys by delivering the same siRNA using a lipid-based nanopar-ticle delivery system designed by Protiva Biotherapeutics, Burnaby, British Columbia (Nature 2006,441,111).
"As optimistic as we all are about delivery, there's a lot of hard work left to do if we want to deliver outside of the liver," says Phillip D. Zamore, who studies RNAi at the University of Massachusetts Medical School, in Worcester. Still, "delivery to the lung looks promising," Zamore points out. And even if there is more work to do to target other organs, "if you can deliver to lung and liver, there's plenty of human suffering you want to alleviate in those tissues."
John J. Rossi, a molecular biologist at the Beckman Research Institute at City of Hope in Duarte, Calif., thinks the problems are closer to being solved. "A number of good strategies have been published in the last year and a half that suggest we have a bunch of choices now" for systemic siRNA delivery, he says, including lipid nanoparticles, 2 cyclodextrin-based polymers, and £ RNA ligands called aptamers.
"We do not believe there is go- I ing to be one universal delivery
solution," says Nagesh Mahanthappa, senior director of business development and strategy at Alnylam. Instead, it will be important to create a "palette of technologies" from which to choose on the basis of the disease and cell type.
Although systemic delivery is universally accepted as key to RNAi therapeutics, one aspect of it is still being debated, and that is whether siRNAs should be chemical ly modified when delivered.
Chemical modifications are essential when therapeu tic siRNAs are introduced without a delivery vehicle. Such modifications are intended to boost the siRNA's stability in the blood by protecting the RNA from
ANALYSIS Weimin Wang performs NMR studies to understand the pH-dependent structural changes in Sirna's lipid nanoparticles.
enzymes known as nucleases, which chew up nucleic acids, and to prevent the siRNAs from triggering an immune response. But experts disagree whether such modifications are necessary when the siRNA is protected by a delivery system.
"Any time you do a chemical modification of the siRNA, that's not RNA any more," says Mark E. Davis, a chemical engineering professor at California Institute
of Technology who is working on a cyclodextrin-based siRNA delivery system. The modified siRNA degrades into molecules that aren't naturally found in the body, making the decomposition products an additional safety concern, he notes.
Properly designed delivery systems can mask the unmodified siRNA so that it can reach the cell without causing immune responses, he says. "We have performed careful studies over the past two years to confirm the surprising observations of several groups that non-chemi-cally modified siRNAs can provide gene inhibition" that lasts as long as that due to chemically modified siRNAs, Davis says.
According to Steven C. Quay, chairman, president, and chief executive officer of Nastech Pharmaceutical, in Bothell, Wash., siRNAs do not have to be any more stable than is required for them to reach their target cells. "If you have an effective delivery system, so that you
of ownership.
sample preparation and laboratory automation.
WWW.CEN-0NLINE.ORG
Extensive line of instruments, automation, columns, software, accessories, reagents and consumable products set the industry mark for use in chromatography analyses,
ι8 NOVEMBER 13. 2006
Metrohm-Peak, LLC Houston, TX 800 410 7118 www.mp-ic.com [email protected]
ο en Ο £ Ο Ζ ο Lu ζ α < h-< Lu
c h -Lui z> ο LU cr
saiMiaia to use.
area to maintain.
LOW COST
www.mp-ic.com
11 K i t M 1 1 1 I P #lCf* I É.1
ion chromatography
get delivery when the material encounters the proper cell, you don't really need to have hours and hours of stability in the blood stream," he says. "To my mind, a delivery system that creates stability in the bloodstream of 24 hours simply means that it doesn't get into cells."
Lieberman thinks that modified RNA may even be a disadvantage inside the cell. "The natural machinery was developed for unmodified siRNAs," she says. "Once you modify them, you're going to interfere with the efficiency. However, there maybe some small modifications that will buy you better specificity and reduce certain kinds of toxicity."
RESEARCHERS at Sirna see things differently Work at that company demonstrates the "critical need for modification" even with efficient delivery, Polisky says. "The cell contains very potent nucleases that can degrade these RNAs inside the cell," he explains. Another difference between modified and unmodified RNA is in duration of effect, he says. Sirna compared the duration of effect of modified and unmodified siRNAs delivered with lipid nanopar-ticles. "We saw very dramatic differences in performance, where the modified RNA was very superior."
In addition, Polisky says, the modified siRNAs may avoid triggering an immune response. He explains that double-stranded RNA can elicit an immune response that involves the secretion of chemicals known as cytokines. "If we modify the RNA the way we have traditionally modified it, we actually can suppress this phenomenon very dramatically," he says. "The cell doesn't really sense the presence of these chemically modified double-stranded RNAs as an alarm signal." Polisky believes that the cytokine response maybe largely responsible for off-target effects seen with siRNA.
Even though the debate on chemical modification is not yet settled, researchers at companies and in academia are working on a variety of delivery systems. The most developed are lipid-based nanoparticles.
Alnylam and Protiva used Protiva's SNALP (stable nucleic acid lipid particles) technology to deliver siRNA targeting the apoB gene in monkeys. These lipid particles consist of cationic lipids, lipids that can fuse with cell membranes (so-called fusogenic lipids), lipids conjugated to polyethylene glycol (PEG), and the siRNA. The ratios of the lipid components can be varied to change the cell type that takes up
4 siRNA
the particle. The length of the PEG-conju-gated lipid affects the circulating half-life and tissue distribution of the particles. Rather than loading siRNA into preformed delivery vehicles, the particle is assembled around the siRNA.
"We were the first group to demonstrate that one could administer an siRNA in a nonhuman primate and see silencing of a target gene," says Alnylam's Mahanthappa. "In this particular study, the liposomes were optimized for uptake by liver cells, but I think liposomes will prove to be a broadly applicable technology."
Sirna is also working on a lipid nanopar-
C leaved mRNA
tide that encapsulates the siRNA. "These lipids are designed to change under certain biological conditions," says Chandra Var-geese, vice president of delivery at Sirna. The lipid nanoparticles are taken up by the cells via endocyto-sis, a process by which materials are brought into cells inside acidic vesicles known as endosomes. Once inside the endosomes, the nanoparticles' lipids un-
SNIP, SNIP siRNA, shown here conjugated to a targeting molecule such as cholesterol, enters the RISC complex and guides mRNA to be cleaved, leading to mRNA degradation and gene silencing.
Quanta BioDesign, Ltd.
Leading Innovator and Producer of
Monodisperse dPEG™e
Vital NEW Chemistry Tools for Your Biological Systems Application Needs!
Use our monodisperse dPEG™s as precise solutions to poor water solubility, high non-specific binding, problematic
immunogenicity and related issues!
Our Unique dPEG™
Heterobifunctionals
CREATE
unbelievable conjugates!
// MAi χ = 2,4,6,8,12 or 24
H
χ x-2,4, 6, 8, 12, 24; R = H, Fmoc, t-boc
... a variety of Amino acid derivatives (peptide synthesis, too!)
Ο
x = 4,8,1Z24;alsow/arinecndMAL
QuantaBioDesign.com Fax Your Orders to (614) 760-9781 or E-mail PO to sa les@quantabiodes ign.com
WWW.CEN-0NLINE.ORG
CO
< ο
< ce < Χ CL
<
<
Cell Interior
RISC
mRNA
. . . d i s u l d u c i a u i i u
modification reagents
α ο £ ο ζ ο u_ Ζ Ο
< l·-< LU Οΐ-Ο ι— 00 LxJ
Ο Lu
19 NOVEMBER 13, 2006
NUCLEIC ACID DELIVERY
Digging Deep To Understand siRNA Delivety When chemists get involved with sIRNA delivery, they want to do more than just find new materials to take therapeutic nucleic acids to their targets. They want to understand how those materials work. "The field of nucleic acid delivety has matured to the point that we need to be asking fundamental questions rather than empirical questions/* says David Putnam, assistant professor of biomedical engineering at Cornell University.
Putnam, like many other chemists, is using materials originally developed for DNA delivery as a jumping-off point for finding new siRNA delivery agents. He is finding distinct differences in Hie behavior of DNA delivery polymers when used with siRNA compared with DNA. "The structures that work well far DNA delivery work only in a very narrow window for siRNA deHveryr he says.
For example, polyethy1eneimine(PED is used to deliver DMA over a wide range of formulations but is "much more finicky for siRNA delivery," Putnam says.
Putnam is now inekiflg libraries of polymers to determine their structure* actfvtty relationships as deNvery vehicles. He s tam wrm a rnethacrylate back-b<Mie with side chains to wh^t he can add a variety of other molecules such as sugars and lipids. "When you start doing combinations, asking how tilings work
OCH
NH?
S ^ Ν ^ Λ , ^ , Ν ^ . ^
became inteteelwp InslRNA detwery ager^whenhev#af>deredovertothe ne^hboring lab of bfefcDgy professor Fabto Piano. - It stmck meimmediately that we could develoo imOcoved chemi-cat tools to solve I M r &géfefaift$r Kirsh-enbeumsays.
Kirshenbaumusespeptidomimetk: oligomers called "lipi-toids" which are conjugates of oJigomeric cationic N-substituted glycines catted "peptoids" and lipid head groups that
2006,£3tt>.Upitokis
for DNA delivery by Ron-aM4^3Bf|AeiiQa^at Chiron Corp.
Kirshenbaum is interested in exploring the relationship between pep-
tokl composition and the nature of the nanoparticles formed with siRNA. "VVe think there's a lotef i e a ^ ^ M p e t t i g questions to ask regaitfeig^^ie jtfirtetloii of the composition, thes*rtictwm of ^ ^ generated nanoparticles, and their ability to provide for ceii uptake.**
For unsurpassed quality and
great pricing, Dishman keeps
pace with your next project.
• Contract Research • Contract Manufacturing
of Intermediates and APIs • ISO 14001 • cGMP/FDA Inspected
Phone:(732)560-4300 Fax:(732)560-4343 E-mail: [email protected] Web Site: www.dishmangroup.com
dishman USA
WWW.CEN-ONLINE.ORG 2 0 NOVEMBER 13. 2006
Dishman accelerates your product
with ingenuity and innovative technology.
550 Union Avenue Suite 9 * Middlesex. NJ 08846
ο ai Ο <ϊ Ο ζ: ο ϋ_ ζ Ω < Ι — < Lu cr ο
ι— 00 Lu Ζ)
LU cr
coftectlvely, the nuiiiborwiHâterials you · need to synthesize gets very large very
; fMt Kirshenbaum; a chemistry pro-lessor at New Y&tk Univ$r$ity,is also focusing on a material that has been showntoworfcwtthDNA.Kifshenbaum
Kirshenbaum hopes to understand the physioochemtcal characteristics that give enhanced activity and then use that knowledge to generate a range of deiivery reagents for siRNA.
"Our goal is to develop a platform that would allow us to create a library that could be used in different settings or for delivery to different cell types" he says. Such a library would allow him to mix and match off-the-shelf slRNAs and delivery agents.
Developing new siRNA delivery systems requires "a more sophisticated approach" than people have been using, Kirshenbaum says. MA big part of that is going to come from improving the understanding of siRN As and chemical modifications to the RNA molecules, but I think there's also a huge opportunity for modulating the characteristics of delivery agents* as ÙMktt**
A. James Mixson, a professor of molecular medicine at the University of Maryland, Baltimore, Is focusing on $o*caiM braneried HK are composed of Wstidines and lysines. Such peptides have been used in the past for DNA delivery. By increasing the ratio of histkiine to lysine and Increasing the nurr^r of branches from four to eight, Mixson's team can Impttw delivery of siRr4A.
The lysine reskkies make the HK peptides positively charged at physiological pH, thereby allowing the pep-tides to complex the siRNA tightly enough to get into cells through en-dosomes. Once the siRNA-HK peptide complexes are inside the cells, the basic Imidazole groups on the histi-dines buffer the endosomes, which are slightly acidic.
"The precise mechanism is not really known, but buffering plays an essential role in the lysis of the endosomes," Mixson says. "If we add a single additional lysine to each of the branches, it can dramatically decrease the siRNA delivery."
Mixson is currently working with Intradigm, an RNAi company In Rock-ville, Md., to develop the HK peptides as siRNA delivery agents by modifying them with polyethylene glycol and targeting ligands.
dergo pH-dependent changes that disrupt the nanoparticles and release the siRNA.
Sirna has started to engineer lipid nanoparticles that target tissues other than the liver. The system is "in advanced stages for certain targets like the liver, and it's in early stages for other targets," Polisky says.
Yet another company developing a lipid nanoparticle-based delivery system
is Berlin, Germany-based Atugen. The company's Atuplex system consists of a cationic lipid and a fusogenic lipid that can disrupt the endosomal membrane. The company has generated a panel of lipid nanoparticle formulations that target different cell types.
Not all nanoparticles used for siRNA delivery are lipid based. The cyclodextrin
Matrix Maker" A u t o m a t e d Preparat ion of Formulat ion Matr ices
Break through your formulation bottlenecks with the liquid-handling
capabilities of the Matrix Maker™ by Emerald BioSystems.
• Dispense a 96-formulation matrix from up to 60 stock liquids in as little as 30 minutes
• Incorporate aqueous, organic, viscous, and low surface tension liquids of varied pH
• Dispense into any user-defined container (tubes, bottles, blocks, etc.)
The Matrix Maker™ is the formulation engine used by Emerald BioSystems to reliably produce all of our commercially available reagent kits.
Emerald BioSystems can help streamline your formulations operation with sophisticated laboratory automation, software tools and consumable products. Call today or visit our website to learn more.
<^Emerald BioSystems Integrated solutions for biotechnology
7869 NE Day Road West I Bainbridge Island, WA I 98110 (888) 780-8535 I (206) 780-8535 I [email protected]
© 2006 Emerald BioSystems
WWW.CEN-0NLINE.ORG 2 1 NOVEMBER 13. 2006
en Ο <Z Ο z: ο u_
Q < I— < LU en Ο
I -co Lu Ζ) ο LU
IVAVAMdiiMfeiriWrtWMMitMfll l l
COVER STORY
nanoparticle delivery system of Calando Pharmaceuticals, Pasadena, Calif., uses cyclodextrin-based polymers developed by Davis, one of the company's founders. In the delivery system, a cyclodextrin-con-taining polycation is mixed with a conjugate of adamantane and PEG and a separate three-part conjugate of adamantane, PEG, and a targeting ligand. The adamantane forms an inclusion complex with the cy-clodextrins within the polycation, allowing noncovalent incorporation of the PEG-con-taining components within the complex.
'We prepare our formulations by pre-mixing the three delivery components in one vial and adding this mixture to a solution of siRNA in another vial," says Jeremy D. Heidel, vice president of research and development and chief scientific officer at Calando. "This formulation strategy gives us the potential to 'mix and match* various targeting ligands and siRNAs." Heidel presented data at the Oligonucleotide Therapeutics Society (OTS) meeting in New York City last month showing that that multiple doses of Calando's formulation, which employs unmodified siRNA, could be safely
@[31§^!Λ@§ Dess Martin Periodinane (Triacetoxy period inane, 1,1,1-tris
(acetyloxy) -1,1-dihydro-1,2-benziodoxol - 3- ( 1Η ) -one )
AcON,°Ac . , - ^ O A c Cc?
Mild reagent for the oxidation of primary & secondary alcohols to aldehydes and ketones. Faci l i tates high y ie ld preparation of multi-functional, complex stereo chemical molecules. It is possible to scale-up the oxidation process to an industrial scale. Due to its highly selective properties, a wide range of useful applications are possible. In some specific cases, it is the only agent capable of the desired oxidation.
Avai lable f rom 1 Oc t o 1 Okc
ORGANO FINE CHEMICALS 207, Anand Bhuvan, Princess Street, Mumbai - 400 002. INDIA
Tel.: 2201 69 68 / 2206 75 21 · Fax: 2205 92 99 / 2208 31 84 Email: [email protected] · Website: www.organo.in
We solicit your proposal for CUSTOM SYNTHESIS & TOLL MANUFACTURING
Y o u r r e l i a b l e p a r t n e r i n F I N E C H E M I C A L S
BUMPY Cyclodextrin-containing polymers form complexes with siRNA that appear as bumps in this AFM image.
administered to monkeys and not cause immune responses.
Another class of delivery system involves simply conjugating the siRNA to another molecule, such as cholesterol or peptides or even another RNA molecule.
One such delivery system is a peptide-based method developed by Nastech. The peptides are conjugated to pieces of double-stranded RNA that are 25 to 30 nucleotides long, which is slightly longer than typical siRNAs. These longer nucleotides are substrates for the Dicer enzyme, which, as its name implies, is responsible for cutting double-stranded RNA into the short pieces that work with the RISC complex. Thus, after delivery, the peptide gets cut away in the process of liberating the siRNA that will knock the targeted gene down.
Nastech has two RNAi therapeutic programs, both of which use this delivery method. One targets tumor necrosis factor α in rheumatoid arthritis, and the other targets genes in the influenza virus.
Meanwhile, two academic groups have recently shown that RNA ligands called ap-tamers can be used to guide siRNAs to their targets. Andrew D. Ellington of the University of Texas, Austin, and Bruce A. Sullen-ger of Duke University have independently demonstrated the use of aptamers to target siRNA to prostate cancer cells.
The groups chose different previously identified aptamers that target the same receptor found on prostate cancer cells. Ellington connected the aptamer to the siRNA via a biotin-streptavidin link (Nucl. Acids Res., DOI: io.i093/nar/gkl388). Sullenger's group connected the two RNA
molecules via a double-stranded RNA linker (Nat. Biotechnol. 2006,24,1005).
Ellington has thus far demonstrated the aptamer-mediated delivery only in cell culture, but Sullenger's group has progressed to a mouse model of prostate cancer. Speaking at the OTS meeting, Sullenger said that although the aptamer delivery is not yet quite as good as lipid delivery, significant reduction in the translation of the targeted gene is still possible.
In addition to protecting the siRNA, delivery systems can also escort the siRNA to specific cells. The importance of such targeted delivery varies with the gene of interest. In some cases it's a necessity and in others simply a bonus, but it's probably desirable in all cases.
"Cell-specific delivery provides enormous advantages, both in terms of the concentration or the dose of siRNA you need to get a therapeutic effect as well as the likely reduction in possible side ef-
UPTAKE Lipid nanoparticles (red) decorate a mouse liver vein. Cell nuclei are stained green.
fects and toxicity," Lieberman says. If the gene is expressed only in certain
cells, the siRNA will be effective only in those cells. In that case, side effects are probably not an issue. For genes that are expressed in many cells but are a problem only in a subset of those cells, the delivery method should home in on those cells to avoid knocking the gene down elsewhere.
A number of different types of targeting ligands are being investigated. Nastech's peptides serve as targeting ligands. Likewise, Calando is currently using the transferrin protein with its cyclodextrin delivery system to target receptors on the surface of cancer cells.
Lieberman is examining the use of fusion proteins made of antibodies and protamine, a protein that condenses nucleic
WWW.CEN-ONLINE.ORG 2 2 NOVEMBER 13. 2006
i 1
Ζ LU
Ο
<
Οι-Ο
< Ο ο LL. ζ Û
< ι— < LU CZ Ο
\-00 LU
= > Ο LU
©mêtëwn®
acids, as simultaneous delivery and targeting agents. Because the fusion protein forms a noncovalent complex with the siR-NA to be delivered, the same reagent can be used to deliver any siRNA. Such constructs have been shown to deliver siRNA to cells infected with HIV (Nat Biotechnol. 2005, 23> 709)· Lieberman is currently developing reagents to target different blood cells and immune cells. She has licensed the technology to Alnylam.
Although most siRNA delivery solutions are chemical in nature, "there are also engineering solutions," Mahanthappa says. "A good example of that is our partnership with Medtronic. We're exploring the use of Alnylam's RNAi technology with Medtron-ic's medical devices to deliver siRNAs directly into the central nervous system." The partnership is focused on treatments for neurodegenerative diseases such as Huntington's and Parkinson's diseases.
But delivery methods are pointless without therapeutic targets. Some of the initial therapeutic targets of siRNA are infectious diseases, particularly those caused by viruses. 'Viruses are a good choice for RNAi
drug development," Lieberman says. A virus offers gene targets that are specific only to the viral disease, and silencing a viral gene affects only the virus. By contrast, treating metabolic diseases by targeting certain human genes could have the unintended effect of silencing genes that are necessary for normal health. "There are very few viruses for which we have really good drugs," she adds.
At the OTS meeting, Ian MacLachlan, chief scientific officer of Protiva, reported his company's progress in developing an siRNA treatment for Ebola virus. The system, currently being tested in a guinea pig model, targets the viral gene for an enzyme known as L-polymerase. To treat Ebola at the earliest stage of the infection, the Protiva scientists are targeting dendritic immune cells in the blood rather than hepatocytes in the liver, but to treat later stages of the disease, they will also need to reach liver cells. "The formulation is a compromise between accessing blood cells and liver cells," MacLachlan said.
Sirna is also working on targeting a virus, namely hepatitis C. Because of the lack of an animal model of hepatitis C, the
company is currently working with a hepatitis Β mouse model, according to David V. Morrissey, senior director of antiviral therapeutics. Speaking at the OTS meeting, he reported that Sirna is getting a sustained knockdown of the hepatitis Β virus in these mice from a dosing regimen of two doses in the first week, followed by one dose a week after that. Sirna's hepatitis C clinical candidate uses a mixture of two siRNAs, and it targets sites that are found in more than 96% of clinical hepatitis C samples.
Next year could see the first clinical trials of RNAi therapeutics packaged in delivery systems. Calando hopes to start Phase I clinical trials for cancer by the end of 2007. Similarly, Sirna and Atugen both plan clinical trials of therapeutics based on their nanoparticle delivery systems, Sirna for hepatitis G and Atugen for cancer.
"Next year could be aninterestingyear in the sense that actual delivered siRNA could be moving into the clinic," Davis says. "It's nice to see all the data in animals, but it's a huge jump to move to the clinic with these synthetic systems. Someone getting to the clinic, that's a whole newballgame." •
Desist ». ·0#»ί ϊ«ηΐ .com
27 McCullough Drive Newcastle, DE 19720 Phone: 800-429-0116
Fax: 302-323-4879
"Ce: ce: ~ m 2-446 2-184
NC
Ν Ν n Η
4-135
N Η
4-139
M e O ^ / ^ C H O C I ^ / ^ X H O B i v ^ ^ C H O Ι γ ^ Χ Η Ο
M ^ H ^ ^ M ^ ^ * l ^
2-411
I
2-382 2-347
CHO
2-381
àc " ^ "-à ce: ^ "CI
2-268
n Η
4-125
Ν
2-148
^NH2
" Ν " "CHO
2-307
Structure Search Our Online Database
0HC
4-124 4-177' 4-134 4-137
Survival initiates from design to composition and concludes with high quality manufacturing of fine chemicals. Survival provides the edge to its Customers by its
expertise in developing specialty chemicals at an unexpected turnaround time and with a class of service and skills. We manufacture chemicals utilizing our in-depth
experience and passion to provide you with the best results.
Ο or Ο
Ο ζ ο Ll_ ζ Ω < I -
< UJ (Τ Ο Έ \-cn LU Ζ) Ο LU
or
Catalog Of Advanced Intermediates www.adesisinc.com info '" adesisinc.com
C3
Ο £ Ο ζ ο υ_ ζ Ο < h-< Lu ο: Ο Έ \-c/) LU
Ο UJ cr
VV ν (Ι Ρ ί ί η Γ ν\ ο cl ο s i ί> η \\ c ( ο ιη ρ ο s r at s il r v i ν a I
WWW.CEN-0NLINE.ORG 23 NOVEMBER 13, 2006