Biotech leaders call for free press

To the Editor: We, the undersigned, are biotechnology executives, entrepreneurs, academic leaders and investors. We are gravely concerned about trends in the United States that are undermining our news media, such that more than 300 news publications across the country recently found it necessary to run coordinated editorials in defense of the First Amendment’s guarantee of freedom of the press.

Why do we, in particular, feel compelled to speak out? We dedicate our lives to discovering and developing new medicines. In recent years, we have witnessed astonishing advances in medicine, including treating diseases at the level of genes and cells. These modern miracles rely, more than anything else, on the free and public exchange of ideas. This encompasses the ability to collaborate, debate, and test one another’s ideas and findings, and to publish data regardless of political, religious or other external pressures or considerations. This is foundational to the scientific method, without which we all might still be living in caves and have an average life expectancy of 30.

The Framers of the US Constitution understood this well; in 1774, the First Continental Congress wrote, in the Appeal to the Inhabitants of Quebec:

The last right we shall mention regards the freedom of the press. The importance of this consists, besides the advancement of truth, science, morality, and arts in general, in … its ready communication of thoughts between subjects, and its consequential promotion of union among them, whereby oppressive officers are shamed or intimidated into more honorable and just modes of conducting affairs.

We believe it is critical to recognize that a free press is not equivalent to a perfect press. Reporters, just like scientists and every other variety of human being, at times make mistakes, can be biased, or may be just plain wrong. We see no compelling evidence to indicate that this is more prevalent now than it was 250 years ago at the time of our country’s founding, or any time thereafter.

The great virtue in having a free press is that everyone’s mistakes, including those of politicians, scientists and the press itself, have the opportunity to be exposed and ultimately corrected. Thomas Jefferson, who, like many presidents, chafed under the scrutiny of the press while he was in office, nevertheless wrote: “Our liberty depends on the freedom of the press, and that cannot be limited without being lost.” To consider our press “the enemy of the people” is antithetical to this key founding principle of our nation.

Technology now provides near instantaneous access to almost every vehicle for news; perversely, this has created more silos of news consumption, as we citizens receive news from outlets that are tailored to our particular tastes and prejudices, and we are less and less frequently exposed to alternative perspectives.

The progress of science and medicine requires that their practitioners not only be exposed to, but actively seek out, such perspectives. This is just as true for the progress of our country and our citizens at large. For America to remain the world’s foremost beacon of liberty and human progress, as well as the world’s leader in science and medicine, we must be resolute in upholding the rights guaranteed us by the First Amendment. 


This letter represents solely the individual and personal views of the authors and signatories, and not those of their employers, companies, universities or any other organization or agency.


John Maraganore is CEO and board member of Alnylam Pharmaceuticals, and on the board of Agios Pharmaceuticals and the Biotechnology Innovation Organization. Steve Holtzman is president, CEO and board member of Decibel Therapeutics, and on the board of Molecular Partners. Ron Cohen is president and CEO of Acorda Therapeutics and a board member of VBL Therapeutics. Jeremy Levin is an officer at Ovid Therapeutics and on the board of Lundbeck A/S, Biocon Limited and ZappRX.

John M Maraganore1, Steven Holtzman2, Ron Cohen3& Jeremy M Levin4

Signatories to the statement

Michael Aberman5, Chris Adams6, Julian Adams7, Jeffrey Albers8, Bonnie Anderson9, Mara G Aspinall10, James E Audia11, Martin Babler12, David Baltimore13, Stephane Bancel14, Peter Barrett15, Zoe Barry16, David Bartel17, Jean-Jacques Bienaime18, Burkhard Blank19, Robert I Blum20, Daniel M Bradbury21, Eugene Braunwald22, John P Butler23, Bruce Carter24, Gustav Christensen25, Isaac Ciechanover26, Chip Clark27, John K Clarke28, Michael D Clayman29, Jeffrey L Cleland30, David Clem31, N Anthony Coles32, Charles L Cooney33, Robert K Coughlin34, Zoltan Csimma35, Sally J Curley36, Bassil Dahiyat37, Daniel A de Boer38, Elisabet de los Pinos39, Ronald A DePinho40, Douglas Doerfler41, Daniel Dornbusch42, Richard H Douglas43, Deborah Dunsire44, Neil Exter45, Nima Farzan46, Jean-François Formela47, Robert Forrester48, Maureen N Franco49, Cedric Francois50, Heather Franklin51, Scott Garland52, Simba Gill53, David V Goeddel54, Maxine Gowen55, Kurt Graves56, Mary Ann Gray57, Barry Greene58, David-Alexandre C Gros59, Faheem Hasnain60, Michael Hammerschmidt61, Elma S Hawkins62, Russell Herndon63, Paul Hastings64, Andrew Hindman65, Annalisa Jenkins66, Cigall Kadoch67, Emil D Kakkis68, Johanne Kaplan69, Laurie Keating70, Rachel King71, Vanessa King72, Scott Koenig73, Peter Kolchinsky74, Daphne Koller75, Marc Kozin76, Paul Laikind77, Robert Langer78, Donna L LaVoie79, John J Lee80, Jonathan Leff81, Alan Levy82, Judy Lieberman83, Christine Lindenboom84, David R Liu85, Uri Lopatin86, Ted W Love87, David N Low Jr88, Nagesh K Mahanthappa89, Tony Martignetti90, W Eddie Martucci91, Kiran Mazumdar-Shaw92, Tracey L McCain93, Corey M McCann94, David J McLachlan95, David Meeker96, Ravi Mehrotra97, Steven J Mento98, Rachel Meyers99, Gregory Miller100, Ken Mills101, Kenneth I Moch102, Michael M Morrissey103, Robert Mulroy104, Imran Nasrullah105, William J Newell106, John F Neylan107, Bernat Olle108, Eric T Olson109, Douglas E Onsi110, John E Osborn111, Julia C Owens112, Stelios Papadopoulos113, Steve Paul114, Brian J G Pereira115, Doris Peterkin116, Cary Pfeffer117, Mark Pruzanski118, Gerald E Quirk119, Michael Raab120, Paula Ragan121, Amit Rakhit122, Bill Rastetter123, Ron Renaud124, Jason P Rhodes125, Scott M Rocklage126, Michael Rosenblatt127, William J Rutter128, Camille Samuels129, James Sapirstein130, Amar Sawhney131, David Scadden132, George Scangos133, John A Scarlett134, Stuart L Schreiber135, Paul J Sekhri136, Eric Shaff137, Bennett Shapiro138, Thomas Shenk139, Nancy Simonian140, William Slattery141, Erika R Smith142, Bruce Steel143, Harald F Stock144, Clifford J Stocks145, Michael Su146, Tim Surgenor147, Jean-Christophe Tellier148, Charles Theuer149, Martin Tolar150, Eric Topol151, Beth Trehu152, Akshay K Vaishnaw153, Christi van Heek154, Michael J Vasconcelles155, George P Vlasuk156, Michel Vounatsos157, Christopher T Walsh158, Jane Wasman159, Andrew Weisenfeld160, Yaron Werber161, Christoph Westphal162, Wendell Wierenga163, Terry Winters164, Eugene Williams165, Chuck Wilson166, Peter Wirth167, Kleanthis Xanthopoulos168 & Sanford (Sandy) Zweifach169

1Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. 2Decibel Therapeutics, Boston, Massachusetts, USA. 3Acorda Therapeutics, Ardsley, New York, US. 4New Milford, Connecticut, USA. 5Quentis Therapeutics, Inc., New York, New York, USA. 6Cydan II, Cambridge, Massachusetts, USA. 7Gamida Cell, Boston, Massachusetts, USA. 8Blueprint Medicines, Cambridge, Massachusetts, USA. 9Veracyte, Inc., South San Francisco, California, USA. 10Health Catalysts Group, Tucson, Arizona, USA. 11Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. 12Principa Biopharma, South San Francisco, California, USA. 13Caltech, Pasadena, California, USA. 14Moderna, Inc., Cambridge, Massachusetts, USA.  15Atlas Venture, Cambridge, Massachusetts, USA. 16ZappRx, Boston, Massachusetts, USA. 17MIT/Whitehead Institute, Cambridge, Massachusetts, USA. 18BioMarin Pharmaceutical, Novato, California, USA. 19Acorda Therapeutics, Inc., Ardsley, New York, USA. 20Cytokinetics, Inc., South San Francisco, California, USA. 21Equillium, Inc., La Jolla, California, USA. 22Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 23Akebia Therapeutics, Cambridge, Massachusetts, USA. 24Novo Nordisk (retired), Seattle, Washington, USA. 25Morphic Therapeutic, Waltham, Massachusetts, USA. 26Atara Biotherapeutics, South San Francisco, California, USA. 27Genocea Biosciences, Inc., Cambridge, Massachusetts, USA. 28Cardinal Partners, Princeton, New Jersey, USA. 29Flexion Therapeutics, Burlington, Massachusetts, USA. 30Graybug Vision, Redwood City, California, USA. 31Lyme Properties 2, LLC, West Lebanon, New Hampshire, USA. 32Yumanity Therapeutics, Cambridge, Massachusetts, USA. 33Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 34MassBio, Cambridge, Massachusetts, USA. 35Csimma LLC, Lincoln, Massachusetts, USA. 36IRC, CGIR, LLC, Savannah, Georgia, USA. 37Xencor, Monrovia California, USA. 38ProQR Therapeutics, Cambridge, Massachusetts, USA. 39Aura Biosciences Inc., Cambridge Massachusetts, USA. 40Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA. 41MaxCyte Inc., Gaithersburg Maryland, USA. 42Dornbusch & Company, Oakland, California, USA. 43Aldeyra Therapeutics, Lexington, Massachusetts, USA. 44Lundbeck Pharmaceuticals, København, Denmark. 45Third Rock Ventures, Boston, Massachusetts, USA. 46PaxVax, Redwood City, California, USA. 47Atlas Venture, Cambridge, Massachusetts, USA. 48Verastem, Inc., Needham, Massachusetts, USA. 49Cambridge BioMarketing, Boston, Massachusetts, USA.  50Apellis Pharmaceuticals, Crestwood, Kentucky, USA. 51Blaze Bioscience Inc., Seattle, Washington, USA. 52Relypsa, a Vifor Pharma Group Company, Redwood City, California, USA.  53Evelo Biosciences, Boston, Massachusetts, USA. 54The Column Group, San Francisco, California, USA. 55Trevena Inc., Wayne, Pennsylvania, USA. 56Intarcia Therapeutics, Boston, Massachusetts, USA. 57Gray Strategic Advisors, LLC, New York, New York, USA. 58Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. 59Imbria Pharmaceuticals, Rancho Santa Fe, California, USA. 60Gossamer Bio, San Diego California, USA. 61Science History Institute, Philadelphia, Pennsylvania, USA. 62Redpin Therapeutics, New York, New York, USA. 63Hydra Biosciences, Cambridge, Massachusetts, USA. 64Nkarta Therapeutics, South San Francisco, California, USA. 65Acorda Therapeutics, Ardsley, New York, USA. 66Cell Medica, London, UK. 67Dana-Farber Cancer Institute/Harvard Medical School/MIT/Foghorn Therapeutics, Inc., Boston, Massachusetts, USA. 68Ultragenyx Pharmaceutical Inc., Novato, California, USA. 69ProMIS Neurosciences, Cambridge, Massachusetts, USA.  70Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. 71GlycoMimetics, Rockville, Maryland, USA. 72Virion Biotherapeutics LLC, London, UK. 73MacroGenics Inc., Rockville, Maryland, USA. 74RA Capital Management, Boston, Massachusetts, USA. 75Insitro, South San Francisco, California, USA. 76Naples, Florida, USA. 77ViaCyte, San Diego, California, USA. 78MIT, Cambridge, Massachusetts, USA. 79LaVoieHealthScience, Boston, Massachusetts, USA. 80Decibel Therapeutics, Boston, Massachusetts, USA. 81Deerfield Management, New York, New York, USA. 82Tasso, Inc., Bellevue, Washington, USA. 83Harvard Medical School, Boston, Massachusetts, USA. 84Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. 85Broad Institute/Howard Hughes Medical Institute/Harvard University, Cambridge, Massachusetts, USA. 86Assembly Biosciences, San Francisco, California, USA. 87Global Blood Therapeutics, South San Francisco, California, USA. 88MTS Health Partners, New York, New York, USA. 89Scholar Rock, Cambridge, Massachusetts, USA. 90Inspired Purpose Coaching LLC, Canton, Massachusetts, USA. 91Akili Interactive Labs, Inc., Boston, Massachusetts, USA. 92Biocon Pharma Inc., Iselin, New Jersey, USA.  93Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. 94Pear Therapeutics, Boston, Massachusetts, USA. 95Skyworks Solutions, Inc., Woburn, Massachusetts, USA. 96KSQ Therapeutics, Cambridge Massachusetts, USA.  97MTS Health Partners, New York, New York, USA. 98Conatus Pharmaceuticals Inc., San Diego, California, USA. 99Third Rock Ventures, Boston, Massachusetts, USA. 100Visterra Inc., Waltham, Massachusetts, USA. 101Regenxbio Inc., Rockville, Maryland, USA. 102Cognition Therapeutics, Inc., Pittsburgh, Pennsylvania, USA. 103Exelixis, Inc., Alameda, California, USA.   104PTX Partner Therapeutics, Lexington, Massachusetts, USA. 105Boehringer Ingelheim Pharmaceuticals, Cambridge, Massachusetts, USA. 106Sutro Biopharma, Inc., South San Francisco, California, USA. 107Keryx Biopharmaceuticals, Inc., Boston, Massachusetts, USA. 108Vedanta Biosciences, Cambridge, Massachusetts, USA. 109Marblehead, Massachusetts, USA. 110HealthCare Ventures, Cambridge, Massachusetts, USA. 111BioVentures/Egalet Corporation, Wayne, Pennsylvania, USA. 112Millendo Therapeutics, Inc., Ann Arbor, Michigan, USA. 113Biogen Inc., Cambridge Massachusetts, USA.  114Karuna Pharmaceuticals, Boston, Massachusetts, USA. 115Visterra, Inc., Cambridge, Massachusetts, USA. 116OncoPep, Inc., North Andover Massachusetts, USA. 117Third Rock Ventures, Boston, Massachusetts, USA. 118Intercept, New York, New York, USA. 119Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.  120Ardelyx, Inc., Fremont, California, USA. 121X4 Pharmaceuticals Inc., Cambridge, Massachusetts, USA. 122Ovid Therapeutics, New York, New York, USA. 123Grail/Neurocrine Biosciences/Fate Therapeutics/Daré Bioscience/Regulus Therapeutics, Rancho Santa Fe, California, USA. 124Translate Bio, Lexington, Massachusetts, USA. 125Atlas Venture, Cambridge, Massachusetts, USA. 1265AM Ventures, Boston, Massachusetts, USA. 127Flagship Pioneering, Cambridge, Massachusetts, USA. 128Synergenics, LLC., San Francisco, California, USA. 129Venrock, Palo Alto, California, USA. 130Contravir Pharmaceuticals, Edison, New Jersey, USA. 131Ocular Therapeutix, Bedford, Massachusetts, USA. 132Harvard University/Massachusetts General Hospital, Boston, Massachusetts, USA. 133Vir Biotechnology, Inc., San Francisco, California, USA. 134Geron Corporation, Menlo Park, California, USA. 135Broad Institute/Harvard University, Boston, Massachusetts, USA. 136Lycera Corp., New York, New York, USA. 137Seres Therapeutics, Cambridge Massachusetts, USA. 138Puretech Health, Boston, Massachusetts, USA. 139Princeton University, Princeton, New Jersey, USA. 140Syros Pharmaceuticals, Cambridge Massachusetts, USA. 141Deerfield Management, New York, New York, USA. 142ReNetX Bio, New Haven, Connecticut, USA.  143Equillium, Inc., La Jolla California, USA. 144CognifiSense, Inc., Park City, Utah, USA. 145OncoResponse, Inc., Seattle, Washington, USA.  146Decibel Therapeutics Incorporated, Boston, Massachusetts, USA. 147Red Sky Partners, Cambridge, Massachusetts, USA. 148UCB S.A., Brussels, Belgium. 149Tracon Pharmaceuticals Inc., San Diego, California, USA. 150Alzheon, Framingham, Massachusetts, USA.  151Scripps Research Translational Institute/Molecular Medicine, La Jolla, California, USA. 152Jounce Therapeutics, Inc., Cambridge, Massachusetts, USA.  153Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts, USA.  154Bio Point Group, Punta Gorda, Florida, USA. 155Unum Therapeutics Inc., Cambridge, Massachusetts, USA. 156Navitor Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. 157Biogen, Cambridge, Massachusetts, USA. 158ChEM-H Institute/Stanford University, Stanford, California, USA.  159Acorda Therapeutics, Inc., Ardsley, New York, USA. 160MTS Health Partners LP, New York, New York, USA. 161Ovid Therapeutics, New York, New York, USA. 162TScan Therapeutics, Boston Massachusetts, USA. 163Crinetics Pharmaceuticals, San Diego, California, USA. 164Scottsdale, Arizona, USA. 165ProMIS Neurosciences, Cambridge, Massachusetts, USA. 166Unum Therapeutics Inc., Cambridge, Massachusetts, USA. 167Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.  168Irras, San Diego, California, USA. 169Nuvelution Pharma, Inc., South San Francisco, California, USA.

Alnylam launches era of RNAi drugs

Alnylam’s office in Cambridge, Mass. The company’s Onpattro is the first RNA interference drug.

On August 10, the US Food and Drug Administration approved the first RNA interference (RNAi) therapeutic, a treatment for polyneuropathy caused by transthyretin (TTR) amyloidosis from Alnylam Pharmaceuticals. The go-ahead for Onpattro (patisiran) sees the RNAi field clear an approval hurdle considered unlikely as recently as six years ago, when pharma exited the RNAi field en masse. The US approval, with Europe expected to follow by early September, is “a major milestone,” says Anastasia Khvorova, an RNAi researcher at the University of Massachusetts in Worcester. Onpattro has an excellent safety record, but there are lingering concerns about potential long-term toxicity from newer, more potent RNAi therapeutics. And the field as a whole still faces investor skepticism in the wake of a decade of clinical trial failures.

But Onpattro could prove a very lucrative drug for Alnylam, the clear leader in the RNAi therapeutics field. Transthyretin amyloidosis “is an inexorable decline to death,” says Morie Gertz, a hematologist at the Mayo Clinic in Rochester, Minnesota. “You either have a liver transplant or hope for the best.” Onpattro, in phase 3, met its neurologic endpoint, with 56% of patients showing improvement at 18 months, compared with 4% of patients on placebo (New Engl. J. Med. 379, 11–21, 2018). Before approval, Goldman Sachs analyst Terence Flynn projected $1.8 billion in peak sales. Alnylam is pricing Onpattro at $450,000 average list, dropping to $345,000 after taking into account mandatory discounts for eligible health care organizations. Alnylam is also negotiating discounts in cases where individual patients don’t do well on the drug.

Onpattro is a 21-mer double-stranded small interfering RNA (siRNA) oligonucleotide containing 2´O-methyl modified and unmodified ribonucleosides, with 2´-deoxythymidine dinucleotide overhangs at the 3´ ends, which is encapsulated in a cationic amino MC3 lipid nanoparticle comprising (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA) plus cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and á-(3´-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy polyoxyethylene (PEG2000-C-DMG). Close behind is another type of oligonucleotide drug, a single-stranded antisense molecule from Ionis Pharmaceuticals and its affiliate Akcea Therapeutics. Ionis’s Tegsedi (inotersen) is a 20-mer with five 2´-O-methoxyethyl-modified ribonucleotides at each terminus, a central region of ten 2´-deoxynucleotide residues, a full phosphorothioate modified backbone, and all cytosine residues methylated at position 5.  It recently completed its own successful phase 3 trial (New Engl. J. Med. 379, 22-31, 2018). With either drug, “you can slow and in some instances actually reverse the disease,” says Gertz. “It’s a big deal.” Analysts’ projected sales, however, assume strong market preference for Onpattro. The Ionis drug, which caused thrombocytopenia and kidney toxicity in some patients, such that all will require platelet monitoring, received European approval July 11 and has a Prescription Drug User Fee Act date with the FDA of October 6.

Both Alnylam’s and Ionis’s drugs prevent TTR mRNA translation into the transthyretin protein. Transthyretin normally forms tetramers, but in the hereditary form of the disease mutant monomers are released and misfold into amyloid fibrils, which accumulate in the nerves, heart and other tissues. By depleting both wild-type and mutant transthyretin mRNA, Onpattro (and Tegsedi) can arrest disease pathology. Single-stranded antisense binds directly to target mRNA for cleavage by RNase H or occupancy, whereas double-stranded small interfering RNAs (siRNAs) engages the RNA interference silencing complex (RISC), which directs target cleavage. In general, antisense has better cellular penetration properties, whereas siRNA is more potent intracellularly.

A wild card in the battle for market ascendancy is Vyndaqel (tafamidis), an oral drug from Pfizer in New York that works by stabilizing the normal transthyretin tetramer. The European Medicines Agency approved Vyndaqel for hereditary transthyretin polyneuropathy in 2011 (Nat. Biotechnol. 30, 121, 2012), but the FDA failed to follow suit, requesting a second efficacy study. In March 2018 Pfizer announced topline phase 3 results for Vyndaqel in transthyretin cardiomyopathy, another presentation of TTR amyloidosis, which exists on a spectrum. Vyndaqel met its primary endpoint, with the company expected to present full results at the European Society of Cardiology Congress in Munich at the end of August. Alnylam’s stock traded 36% lower in July than in March, a drop that Needham & Co. biotech analyst Alan Carr attributes to the Vyndaqel uncertainty. “We’re all very interested in seeing these data,” Carr said.

Alnylam CEO John Maraganore views Onpattro as the winner in TTR amyloidosis with polyneuropathy. “Tafamidis, based on previous studies, slows down the progression of neuropathy in patients with the disease, but it doesn’t really halt it,” he says. But patients with hereditary TTR amyloidosis with cardiomyopathy, as well as with wild-type TTR disease—in which TTR amyloid slowly deposits in the heartmight be different. Alnylam has aspirations for its second-generation TTR amyloidosis drug, ALN-TTRsc02, which tethers the siRNA molecule to multivalent N-acetylgalactosamine (GalNAc) ligands that bind the asialoglycoprotein receptor on liver cells. The company is hopeful this second-generation molecule will be superior in both indications because it’s more potent than Onpattro, with far more convenient dosing and delivery. Wild-type disease affects about ten times as many people as the hereditary form, so the market stakes are high. “We’re really quite eager to see what the tafamidis results are,” Maraganore said in early August. ALN-TTRsc02 should begin phase 3 by year’s end.

Alnylam’s second-generation drug should eventually supplant Onpattro, which is only approved for hereditary disease. Onpattro uses a delivery system that Alnylam no longer pursues. Double-stranded siRNAs need to evade nuclease degradation and the innate immune response and then enter cells, where they must escape the endosome to load into RISC for sequence-specific cleavage of target mRNAs. Alnylam’s early solution was encapsulation in a lipid nanoparticle (LNP). When the company set out to treat TTR amyloidosis, the LNP was “the only technology that had really been demonstrated to work,” says Rachel Meyers, Alnylam’s former head of research. “It led to a very elaborate discovery effort to optimize it.” The result is an effective drug, but Onpattro is not perfect. It’s still immunogenic enough to require steroid pretreatment to minimize reactions to its 80-minute IV infusions, given every three weeks.

Although Alnylam is no longer developing LNP drugs, some RNAi companies are still pursuing LNP delivery, as are many working on CRISPR–Cas gene editing and therapeutic modified mRNAs. Patisiran’s approval “is a very big step forward for the guys that are going to come behind, in gene editing and mRNA delivery,” says Meyers, now entrepreneur-in-residence at Third Rock Ventures in Boston.

Even before Onpattro entered the clinic, in 2012, Alnylam was looking at GalNAc-conjugated siRNAs as an alternative to LNPs. GalNAc delivery requires extensive modification of the siRNA, as it is no longer protected from nucleases by the LNP. Alnylam eventually worked out a specific pattern of O-methyl and fluoro modifications at the 2´ position of the ribose, along with fewer phosphorothioate modifications (a sulfur substituting for one of the non-bridging oxygens) in the backbone, with spectacular results. In phase 1, a single subcutaneous dose of Alnylam’s GalNAc-conjugated siRNA, ALN-TTRsc02, knocked down 80% of the TTR target for a full year. The drug, says Khvorova, “is very close to perfection.” Alnylam plans to start phase 3 for ALN-TTR02 (with subcutaneous dosing every three months) by the end of 2018. 

Other Alnylam drugs, all for liver diseases, are even further along. The company expects to submit an New Drug Application for givosiran, for acute hepatic porphyrias, by year’s end. Inclisiran, for hypercholesterolemia, and fitusiran, for hemophilia, are in phase 3. (Inclisiran is partnered with The Medicines Company in Parsippany, New Jersey, and fitusiran with Sanofi Genzyme in Cambridge, Massachusetts.). Competitors Dicerna Pharmaceuticals in Cambridge, Massachusetts, Silence Therapeutics in London, UK and Arrowhead Pharmaceuticals in Pasadena, California also have GalNAc-conjugate siRNAs in development. According to Khvorova, the field considers the problem of liver delivery basically solved with GalNAc.

Except, she adds, for a few lingering theoretical toxicity concerns. One is the 2´-fluoro modification. Ionis scientists have reported that treatment of cells with 2´-fluoro-modified antisense oligos results in the off-target binding and knockdown of several DNA repair genes, resulting in cell death in in vitro assays (Nucleic Acids Res. 43, 4569–4578, 2015). A second worry is that high levels of persistent siRNAs might outcompete endogenous microRNAs for RISC loading, with unpredictable biological effects. Finally, superstable siRNAs might accumulate in endosomes and lysosomes, with toxic consequences. “So far there is no indication that there are any issues,” says Khvorova. “But … things can pop up years after you administer a compound.”

Fueling the concern is revusiran, Alnylam’s original GalNAc conjugate for TTR amyloidosis. Alnylam discontinued revusiran in phase 3 because of the high number of deaths in the treatment arm relative to the placebo group (Nat. Biotechnol. 34, 1213–1214, 2016). Alnylam stock plunged 49% on the news. The company’s subsequent analysis could not rule out a drug effect. “The tox was there and the tox was real,” says Khvorova. “That is why we have those lingering concerns.”

“There is reason to believe [the death imbalance] might be a chance occurrence, but we can’t exculpate the drug,” says Maraganore. “That’s unfortunate.” But he points out that the newer, more potent GalNAc compounds use doses 20–100 times lower than revusiran’s. Alnylam also conducted rodent studies showing that 2´-fluoro modifications and RISC loading were unlikely to contribute to liver toxicity from siRNAs at supraphysiological doses (Nat. Commun. 9, 723, 2018). The company will soon move newer oligonucleotides into the clinic that appear to be even safer. These incorporate a single GNA (glycol nucleic acid) into the siRNA’s antisense seed region, the part of the molecule that recognizes the target mRNA, which would reduce off-target base pairing. The company is also developing an antidote to its long-acting GalNAc-siRNA conjugates (Nat. Biotechnol. 36, 509–511, 2018) to shut them off if necessary.

For the moment, Alnylam can savor its first drug approval, the fruit of 15 years of continuous effort. The company survived the pharma backlash of 2008–2011 battered but intact, thanks to an ample cash cushion. “Alnylam was able to weather the storm of pharmaceutical companies being naysayers because they had the resources, plain and simple,” says Meyers. Now the company must build on Onpattro to establish RNAi as a platform technology. After so many failures, says Khvorova, “it will require some more successful stories, not just one patisiran, to rebuild … investor confidence.”

Ken Garber Ann Arbor, Michigan

A new approach for DNA synthesis

Credit: Eduardo de Ugarte, Berkeley Lab Creative Services

Ordering synthetic oligos or genes online is now commonplace and an essential resource to scientists across disciplines. But the phosphoramidite chemistry currently used to synthesize DNA is limited to direct synthesis of about 200 nucleotides, with longer stretches requiring assembly. The capacity to synthesize long stretches of DNA is important for a variety of applications, including DNA storage, DNA origami, and to synthesize DNA containing regions with repeats, which are difficult to put together. In a paper published recently in Nature Biotechnology, Jay Keasling and colleagues report a promising new approach to DNA synthesis. Using a terminal deoxynucleotidyl transferase (TdT) conjugated to a single deoxyribonucleoside triphosphate (dNTP), they tether the primer to TdT after extending it by one nucleotide. This tethering prevents further extension until the dNTP is cleaved by, for example, light. Keasling and colleagues demonstrate synthesis of short oligos, providing proof-of-principle for a method that may in time represent a useful approach to enzymatic DNA synthesis.

Irene Jarchum

Hunting connections between cell types and cytokines

Credit: Denise Feiger Visual Design, Shutterstock

Cytokines are small proteins that mediate signalling among immune and non-immune cells, and they trigger a range of cellular activity, such as proliferation, activation and killing. Over many decades, immunologists have described countless associations between cell types and the cytokines they produce or sense, but many of these findings, although published, are difficult to access. Associations may have been discovered in a particular disease context or cell type, or uncovered as part of a larger study and thus not corroborated or expanded. Work from Shai Shen-Orr and colleagues, published in Nature Biotechnology, aims to unearth these connections and provide a useful resource for enabling new discoveries. The researchers developed a computational tool that mines PubMed data and connects cell types to cytokines and diseases. The text-mining tool, called immuneXpresso, was used to identify connections between 340 cell types and 140 cytokines across thousands of diseases. Shen-Orr and colleagues showed they could corroborate known interactions and discover previously unappreciated connections worthy of further investigation. The resource is openly available and can be accessed here.

Irene Jarchum


Will the EU deregulate gene-edited plants?

At the beginning of the year, the advocate general of the Court of Justice of the European Union (CJEU) issued an opinion that plants created using new plant breeding techniques, including gene-editing platforms like CRISPR, TALENs and the like, are eligible for the so-called mutagenesis exemption. This exemption relates to rules the European Union uses to regulate the release and marketing of genetically modified organisms (GMOs), which are outlined in Directive (2001/18/EC), originally drafted in 2001. The exemption covers any plants considered ‘safe’ or produced using techniques that have a history of safety, including plants derived from traditional mutagenesis (hence the mutagenesis exemption).

Agbiotech and seed companies are now waiting for the CJEU to issue its ruling on the AG’s opinion, which is anticipated in the next few weeks. If the CJEU follows the AG’s opinion, several NPBTs and their resultant products will be exempt from scrutiny under the Directive. Here, a set of authors from Wageningen University and Research in The Netherlands, headed by Kai Purnhagen, outline four options for how the European Union and its member states may implement a new policy overseeing approval of products generated via NPBTs. Most intriguing of all, they suggest the new policy that follows the AG’s opinion would create an opportunity to move EU regulation for new crop varieties to a more scientific, risk-based and decentralized strategy.

The Correspondence PDF is accessible via the link below.






First Rounders: John Maraganore


The First Rounders podcast with John Maraganore can be found here. If you’d like more background on John, read this profile in Xconomy from 2014. Here’s John being interviewed at BIO after being elected chairman of the lobby group. And here’s the Nature paper on RNAi in 2001 that helped crack the field open.

Podcast is sponsored by the Master’s in Biotechnology Enterprise and Entrepreneurship program at Johns Hopkins University.

Is yellow fever back in Brazil?

yellow-chair-1190621-1280x960The answer to this question is, Not exactly. Yellow fever never left Brazil. I earlier wrote that Oswaldo Cruz eradicated yellow fever in Brazil in the 19th century. In fact the extraordinary work done by Cruz focused on yellow fever in urban areas in Rio de Janeiro, but the illness persisted in the jungles.

Basically, there are two kinds of yellow fever. The virus is absolutely the same in both, an arbovirus, but the vectors are geographically different. In the forests the vector is mosquitoes of the genus Haemagogus and Sabethes, and they acquire the virus from monkeys and transmit to humans entering the forests. The monkeys also die of the disease and thus are an important indicator of the presence of yellow fever.

In urban areas the vector is Aedes aegypiti, the same mosquito that transmits the virus that causes dengue, zika and chikungunya in cities.

The issue is that today’s urban areas and forests have boundaries that are more confluent than in the past. Brazil now has 90% of its population in urban areas. People go into the forests, get contaminated by the vectors that acquired the virus from monkeys. Once back in cities, the Aedes vector transfers the virus to others. In Brazil, 846 people have confirmed yellow fever, and 260 have died as of early March, and the number is growing all the time. The Minister of Health says we do not have epidemic occurrence of yellow fever in urban areas in Brazil. Deaths occurred so far because people are contaminated in the forest and may die in urban areas. In fact these are considered sylvatic yellow fever in nature.

Brazilians initially understood the threat from yellow fever, and many sought out the vaccine. Soon the demand outstripped the supply, and vaccines began to be given out at doses one-quarter of the usual amount. It works, but protects for only ten years. Campaigns have been established to vaccinate millions, particularly in the State of São Paulo, and there the supply was adequate because many thought the vaccines could harm them and others didn’t believe yellow fever could cause their death.

Vaccines in Brazil are produced in eggs, an old technology. This takes six months and people allergic to eggs cannot be vaccinated. We need to begin producing vaccines in plants as Medicago is doing in Canada located in Quebec for influenza.

safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers. In areas where yellow fever is common and vaccination is uncommon, early diagnosis of cases and immunization of large parts of the population is important to prevent outbreaks. Once infected, management is symptomatic with no specific measures effective against the virus. Death occurs in up to half of those who get severe disease. In 2013, yellow fever resulted in about 127,000 severe infections and 45,000 deaths, with nearly 90% of these occurring in African nations, according to  Wikipedia.

Also, we have been waiting four years to begin using commercially in Brazil the GM mosquito developed by Oxitec Brasil that has the headquarters in Piracicaba in the State of São Paulo. So far Oxitec Brasil can only release the GM mosquitoes experimentally , celebrating contracts with  the government of counties. This is  because ANVISA, which in Brasil is equivalent to FDA, has not registered the GM mosquito to be released commercially. CTNBio, the Biosafety Commission, approved the release of the GM mosquitoes in April of 2014. It is possible that Aedes does not transmit yellow fever as well as it does dengue, zika and chikungunya. But the problem of yellow fever in urban areas will increase if the population of Aedes increases, and that can be prevented by the GM mosquitoes developed by Oxitec Brasil.

Luiz Antonio Barreto de Castro



Rumen microbial genomics resource

Robert (Bob) E. Hungate developed methods (the ‘Hungate technique') to culture anaerobic bacteria and archaea. These methods are still used in many labs worldwide.

Robert (Bob) E. Hungate developed methods (the ‘Hungate technique’) to culture anaerobic bacteria and archaea. These methods are still used in many labs worldwide.

Special Collections, University of California Library, Davis

The Hungate1000 project, named after one of the great microbiologists, Robert E. Hungate (pictured), was launched with the aim of producing a reference set of rumen microbial genome sequences. When this project began there was only a handful of rumen reference microbial genomes available. The first output of the Hungate1000 project, comprising 410 high-quality genome sequences, is reported online today in Nature Biotechnology. Seshadri et al. highlight discovery of degradative enzymes, biosynthetic gene clusters and Crispr sequences. These reference genomes will enable robust interpretation of rumen metagenomes, which should result in a better understanding of rumen functions. Genome-enabled research into feed conversion efficiency, methanogenesis and cellulose degradation will, in turn, assist development of strategies to balance food production with efforts to minimize greenhouse gas emissions. Finally, access to cultivated Hungate Collection strains will provide vital tools for studying carbon flow in the rumen, breakdown of lignocelluloses and methane formation.

Susan Jones

First Rounders: Jeffery Leiden

Dr. Jeffrey Leiden, Chairman, President and Chief Executive Officer of Vertex Pharmaceuticals photographed in July 2017 for Forbes.

The First Rounders podcast with Jeff can be found here. A Boston Globe article on Leiden taking the CEO position at Vertex is here and one from Xconomy is here. Read the Forbes piece on Vertex’s success in cystic fibrosis.  A profile on Jeff in STAT can be found here. Click here for a video on Vertex’s learning lab.

Brady Huggett

The Developing World Needs GMOs

MudThe need to feed growing populations in developing countries, especially countries in Africa, must be met by increasing the yields of crops. Also, climate-change related problem such as drought continue to worsen hunger problem and humanitarian crisis in the continent. Genetically modified organisms (GMOs) could greatly help with these issues, yet resistance persists in Europe and Africa both.

For several years, I have been thinking about what should be done to address the negative sentiment about GMOs. As an African scientist who has the vast knowledge of biotechnology and understands the potential of the new technology, I took the task upon myself to gather evidence with experts around the world and publish a book and a Correspondence on how to address GMO regulation problems at the international level.

While this was a difficult task, I am proud to be the first African scholar to mobilize experts from around the world to review or abandon current regulatory framework for GMOs. It is uncommon but I have taken this bold step and made an initial attempt to challenge the current status quo of GMO regulation.

Europe is overly cautious about the use of GMOs. But Europeans are well fed, and are not experiencing the type of hunger and malnutrition that affects people in other parts of the world. Europeans must stop playing fear-based politics on technologies that can benefit millions of people dying from micronutrient deficiency and hunger in Africa.

But the problem exists here in Africa, too. Some years ago I travelled to several countries across different regions in Africa to discuss the benefits of GMOs with policymakers. These talks spurred the largest study in the history of GM agriculture in Africa, but the debating continues, with policymakers asking for more evidence to prove GMOs are safe. In my own country, Nigeria, I was threatened in the local news for promoting the use of GMOs. Media reported that eating food made from GMOs is bad for your health and could cause cancer.

We need to stop media bias towards the use of GMOs, and educate the individuals and organizations that are influencing policies against GMOs. There is overwhelming evidence that GMOs are safe for human consumption. If the world is to achieve the United Nations sustainable-development goals, GMOs will need to play a part.

Adenle Ademola