Every drug needs an antidote, and so the Spoonful of Medicine blog has also given readers some light-hearted posts about the research enterprise. We’ve taken on the amusing and bizarre acronyms for clinical trials, such as the ‘AWESOME’ trial, in a story that became a reader favorite. Another popular post detailed the findings of an ancient shipwreck that contained tablets with ingredients similar to what might find in today’s over-the-counter medicine Cold-EEZE.

We are now committing more time than ever before to bring you investigative news features (our piece on missing follow-up clinical trial data is one example) and although that means this blog will be put on pause for the foreseeable future, we will continue to publish news on the Nature Medicine homepage, which underwent a redesign earlier this year. Our first ‘advance online publication’ news story, about how universities are banning medical staff from helping with the Ebola outbreak in West Africa, went live online just recently. There will be more of those to come, and we hope you will subscribe—via Twitter, Facebook or the journal’s table of contents RSS feed—to keep up to date about all the news that we offer. Our news reporting goes far beyond the Spoonful site, and we hope you’ll seek us out at www.nature.com/naturemedicine where the news will keep rolling out.

The job requires an individual who can work with minimal guidance, finding and developing exclusive stories. The ideal candidate will have a degree in biology or a related science and at least two years of experience as a working journalist. S/he should be able to commission and guide freelancers and work with production staff to conceptualize artwork for print layout. The assistant news editor will be based in our Cambridge, Massachusetts, offices and work closely with our team in New York.

The job offers opportunity for travel and attendance at leading scientific meetings, as well as excellent benefits. Nature Publishing Group is an Equal Opportunity Employer.

Please submit a resume, cover letter and any relevant published writing samples to r.khamsi@us.nature.com and https://home.eease.adp.com/recruit/?id=10018071 by 30 July 2014.

Santagata (second from left) and part of his team with the mass spectrometry platform for image-guided surgery in the Advanced Mutimodality Image Guided Operating (AMIGO) suite at Brigham and Women’s Hospital, Harvard Medical School.

It doesn’t get much more complicated than brain surgery. Surgeons tasked with removing brain tumors have limited information available to help them make decisions about what tissue appears cancerous and how much to excise without damaging brain regions important to key functions such as movement and speech.

But decisions about how much to cut might become easier in the near future: A study published today offers a possible way to discern which brain tissue is cancerous and guide surgeons in real time. The research, which appears in the Proceedings of the National Academy of Sciences, uses a technique formerly confined to analytical chemistry labs, called mass spectrometry, to make this determination right in the operating room.

“It’s hard to distinguish normal tissue from tumor,” explains Sandro Santagata, a pathologist at Brigham and Women’s Hospital in Boston and co-author of the study.** Thanks to the new approach, he says, “we’re many steps closer to getting a complete picture at the time of surgery.”

Techniques currently used in the operating room to guide tumor excision, such as tissue pathology and magnetic resonance imaging (MRI), can be costly and time consuming. A surgeon may have to wait 30 minutes for the biopsy results or an hour to perform MRI, adding to surgery time and increasing patient risk.

In an effort to speed up the process, Santagata and his colleagues joined with analytical chemist Graham Cooks at Purdue University in West Lafayette, Indiana, to exploit a hallmark feature of brain tumors as a way of defining the boundaries of these malignancies. As it turns out, brain tumors known as gliomas tend to express high amounts of a lipid metabolite called 2-hydroxyglutarate (2-HG).

According to Dan Cahill, a neurosurgeon at Massachusetts General Hospital in Boston who was not associated with the new study, doctors already use other methods, like polymerase chain reaction, to check tissue for 2-HG levels after surgery to ensure that they have thoroughly excised the tumor. The absence of it in the area immediately surrounding the tumor site means that all of the cancerous cells have been removed. “If you have it [2-HG], you know your margin isn’t clean,” he says. Unfortunately, current methods to detect 2-HG take far too long—about two days—to influence decisions made mid-surgery.

Santagata and his colleagues installed a mass spectrometer in an operating suite at Brigham and Women’s Hospital and analyzed 35 biopsied glioma specimens for the 2-HG metabolite. Although they performed the analysis immediately, the results were not used to inform the surgeons since the research is still in early stages. The mass spectrometry technique used, called desorption electrospray ionization, analyzes the tissue without destroying it, allowing detailed pathology, which is still the gold standard for tumor assessment, to be performed on the same sample. Pathology done for the study confirmed that 2-HG was detected at the highest levels in areas with the most tumor cells.

“I’m hoping we can start incorporating this into therapy for this subset of tumors,” says Nathalie Agar, a neuroscientist at Brigham and Women’s Hospital and co-author of the study. She and Santagata are currently advising the biotech company, BayesianDx, which is trying to develop the technology and bring it into clinical use. It may be years before this technology becomes widespread, but Agar says she is encouraged by this proof-of-concept study.

**Correction (2 July): In an earlier version of this story, Sandro Santagata was referred to as the lead author of the study. He was the first author. Nature Medicine regrets the error.

Since his diagnosis in August of 2013, van Soest has been using his management consulting background to strategize how best to contribute to the ALS community. He soon met two fellow ALS patients and entrepreneurs, Robbert Jan Stuit and Bernard Muller. On 19 May the three launched an ALS-specific investment fund, called Qurit Alliance. Qurit Alliance aims to raise €100 million ($139 million) to then invest into ALS-focused private biotechnology companies and institutions to kick start projects of drug discovery and smarter design drug trials to find ALS treatments.

“This is one of the novel, innovative ventures that wants to make sure orphan disease clinical pipelines do not dry up as the pharma model and venture investment shifts to later stage opportunities,” says Steve Perrin, CEO of the Massachusetts-based ALS Therapy Development Institute.

“Crisis breeds creativity,” notes Melissa Stevens, deputy executive director at FasterCures, a nonprofit think tank based in Washington, DC. “There has been a lot of monetary pressure on the research community with NIH’s purchasing power down by 25% in the last decade and US venture capital funding down by 21% from 2007 to 2013.”

Connections for speed

Although Stuit, Muller, and van Soest do not have a biotechnology background, they do know how to bring experts together. In 2012, Stuit and Muller started a Netherlands-based biotechnology company, Treeway, focused on ALS drug development—the company’s first in-human trial is slated to start by year’s end.

“What we see in the world of biotech, is that start ups really struggle to re-invent the wheel and find capital,” says van Soest. There is a lot of wasted money on duplicated efforts, inefficient processes, and a lack of data sharing in orphan disease research, according to the three founders.

To address these issues and partly mitigate investment risk, Qurit is bringing together prominent ALS researchers from around the world to vet and steer research, biotech company partnerships, and experienced managers to run the fund as part of a focused center of excellence. Operating with a sense of personal and professional urgency, the goal for the fund is to put the investment into action by January 2015. The team, along with Leonard van den Berg, director of the Netherlands ALS Center in Utrecht, is also helping to set up an institution called TRICALS that will include a website platform to lessen the time it takes to execute clinical trials by connecting patients with ALS treatment centers and companies working on drug for the disease.

Similar endeavors focused on specific orphan diseases have also cropped up in recent years. Cydan Development, the first drug accelerator for rare disease, and Kurma Biofund II, the first venture capital fund focused mainly on these illnesses, both launched last year. Other efforts have had a personal motivation like Qurit: Ilan Ganot, a former hedge fund manager, left his job in October 2012 when his two-year old son was diagnosed with Duchenne muscular dystrophy. Since then, he has raised $17 million and in January 2014 started Solid Ventures, a biotechnology company focused solely on acquiring, licensing or partnering on select early stage compounds for the fatal genetic disease—and provide an investment return for investors. John Crowley, who has two children with Pompe disease, started New Jersey-based Amicus Therapeutics, focused on lysosomal storage diseases.

Diagnosed in June 2010 and May 2011, respectively, both Muller and Stuit also call themselves lucky. Their disease has progressed slowly relative to others with the affliction. “When you are diagnosed with ALS today it’s basically a delayed death sentence,” says Stuit. “We are claiming ALS can and will be fixed. The only question is when. And we intend to speed up that process dramatically.”

Cluster of vesicles made by virus from usurped and reshaped membranes.{credit}Volker Thiel, Edward Trybala and colleagues{/credit}

Since its appearance in Saudi Arabia in 2012, Middle Eastern Respiratory Syndrome (MERS) has spread to fifteen countries, including the US, where two cases were confirmed in the past month. Worryingly, about 30% of confirmed cases have been fatal, and the lack of specific antiviral drugs for the MERS-coronavirus (MERS-CoV), which causes the illness, poses a threat to public health.

A new insight could help pave the way to treatments in the future for this type of virus. In a paper published today in Plos Pathogens, clinical virologist Edward Trybala and his colleagues at the University of Gothenburg in Sweden describe a compound called K22 that inhibits coronavirus growth in human cells.

Trybala’s initial goal was to identify drug candidates that inhibit common coronaviruses, such as respiratory syncytial virus, for which there are currently no drugs. In a screen of over 15,000 compounds, K22 stood out for its ability to selectively block a common human coronavirus from reproducing in cultured human lung cells. He then approached Volker Thiel, a virologist from the University of Bern in Switzerland, who studies how host cells interact with coronaviruses. Thiel’s lab produced a recombinant version of the Severe Acute Respiratory Syndrome coronavirus, SARS-CoV, which caused over 700 deaths during an outbreak in 2003 and 2004, and they found that K22 moderately inhibited SARS-CoV replication.

“We were ready to submit our work and then MERS came,” Thiel says, referring to the recent MERS outbreak that began in Saudi Arabia in 2012. They tested K22 on MERS-CoV in cultured human airway epithelial cells—the cells naturally targeted by coronaviruses, and found that it blocked MERS-CoV with even better efficacy than SARS-CoV. K22 also inhibited several more human and animal coronaviruses. This means that its mechanism of action is conserved across the coronavirus species. “It’s clear that there is a new drugable target,” says Thiel.

“I think this is a terrific concept,” says Mark Denison, a pediatric infectious disease specialist who studies coronaviruses at Vanderbilt University School of Medicine in Nashville, Tennessee. “It demonstrates that you can target very highly conserved processes.”

Replication blocker

K22 blocks a critical step in viral replication in which the virus hijacks some of the cells own membranes to build structures called double membrane vesicles (DMVs). The compound hampers the formation of these structures, thus preventing the virus from copying its genome and replicating inside the cell. Although the precise target of K22 is still unknown, there is some evidence that it binds to the viral protein nsp6, which is involved in altering host cell membranes to make DMVs.

Matthew Frieman, a virologist at the University of Maryland School of Medicine in Baltimore, says that a broadly inhibiting antiviral drug like K22 would be particularly effective, but points out that despite the success of many coronavirus antiviral drugs in cell culture, few have worked in animal models. Frieman’s group recently published the results of a screen that tested 290 drugs approved by the US Food and Drug Administration for antiviral activity against MERS-CoV, and is currently testing positive hits in animal models.

According the Thiel and Frieman, the biggest roadblocks to moving coronavirus antiviral research forward are lack of interest and funding. Perhaps the recent dramatic increase in the number of MERS cases will stir up some of both.

Electron micrograph of Ebola virus{credit}CDC/ Frederick Murphy{/credit}

Earlier this year, the Ebola virus popped up for the first time ever in West Africa. How it got there, some 2,000 miles from previous Ebola hotspots in remote parts of Central Africa, remains a mystery. Experts are particularly concerned about the current outbreak, which has sickened more than 250 and killed at least 140, because the pathogen has made its way into Conakry, the densely populated capital city of Guinea.

Unfortunately, there are no vaccines or treatments approved to work specifically against the virus, which first emerged in the forests of Zaire (now the Democratic Republic of Congo) in 1976. The virus’s high virulence and lethality make it challenging to study, and its rarity means that any effective therapeutics that are developed will likely have limited commercial potential, leaving pharmaceutical companies little financial incentive to develop treatments against the pathogen.

Very few candidate therapeutics against Ebola have proven effective in non-human primates, the gold-standard animal model for research against such viruses. But there is, amidst the ongoing outbreak, mobilization of funding toward anti-Ebola agents that have proven their mettle in such models: last month the US National Institutes of Health announced that it was putting a combined total of more than $50 million towards a handful of the most promising approaches.

About half of that money will support a five-year collaborative research effort spanning 20 labs in seven countries to develop a cocktail of antibodies that neutralize the virus. Various research groups have already identified 150 or so neutralizing antibodies against the Zaire strain of the virus, a variant of which is responsible for the current outbreak, says Erica Saphire, a virologist at The Scripps Research Institute in La Jolla who is leading the consortium. The members of the collaboration are “putting all of their antibodies in and we’re going to compare them side-by-side and figure out which ones are best and why,” she says.

Researchers already know that mixtures of neutralizing antibodies can thwart the virus in non-human primates. For example, consortium member Gary Kobinger and his colleagues at the Public Health Agency of Canada in Winnepeg reported in June 2012 that a mixture of three anti-Ebola virus antibodies saved the lives of cynomolgus macaques when administered up to two days after a lethal dose of the virus.

A few months after Kobinger’s study was published, researchers from the US Army Medical Research Institute of Infectious Diseases (USAMRIID) in Frederick, Maryland and San Diego-based Mapp Biopharmaceutical obtained similar results using a different antibody cocktail in rhesus macaques. “Rather than compete against each other, we figured we’d work together to figure out which antibodies from each cocktail are the best,” says Larry Zeitlin, president of Mapp and co-author of the rhesus macaque study who is also a member of the new consortium. Zeitlin says the group’s latest cocktail contains a mixture of two antibodies developed by the Canadian team and one from the US bunch. “We expect to be doing a phase 1 safety trial in the first half of 2015,” Zeitlin says.

A bevy of options

The other half of the new funding the NIH announced last month is going toward a multi-center collaboration led by Ebola researcher Thomas Geisbert at the University of Texas Medical Branch in Galveston. The five-year effort brings together academic researchers and scientists from Profectus BioSciences in Baltimore, Maryland, and Canada’s Tekmira Pharmaceuticals. The partnership aims to advance several different types of therapeutics for Ebola virus and the related Marburg virus, which also causes hemorrhagic fevers in humans.

One of the group’s candidate therapeutics is a vaccine containing a form of the vesicular stomatitis virus (VSV) engineered to contain a gene from the Zaire strain of the Ebola virus (they’ve also devised similar vaccines for Marburg virus as well as a different strain of Ebola virus). Geisbert’s lab has shown that a single shot of the vaccine saves rhesus macaques from a lethal dose of Ebola virus.

For their part, Profectus is investigating the prophylactic effectiveness of the vaccine, and is applying for funds to test the VSV-based Ebola vaccine in humans, according to John Eldridge, the company’s chief scientist. Profectus has already tested VSV-based vaccines against HIV in humans, Eldridge says, “so we know the vaccine vector is safe and immunogenic.” Still, Geisbert points out that “for any of these vaccines, we’re talking years from being ready to use in humans.”

However, another therapy Geisbert’s group is investigating may be ready sooner. It’s an RNA interference (RNAi)-based drug that silences certain genes in the Zaire strain of Ebola virus. The treatment, developed by Tekmira and known as TKM-Ebola, protected rhesus monkeys from a lethal dose of the virus. Backed by $140 million from the US Department of Defense, the company began phase 1 tests of TKM-Ebola in healthy human volunteers in January. And in early March, the FDA gave the drug fast-track status to expedite its development.

Geisbert’s team will also investigate combination therapies, such as Profectus’s vaccine given in combination with Tekmira’s RNAi drug. “Combinations may work more effectively or more efficiently than any approach alone,” Eldridge says. “I don’t think anyone’s presumptuous enough to think they have the answer all by themselves.”

All treatments, big and small

Most of the proposed Ebola treatments target a single strain of the virus. But one team of researchers at the USAMRIID and North Carolina-based BioCryst Pharmaceuticals has been working on a small molecule with broad antiviral activity. The compound, BCX4430, blocks the replication of RNA viruses like Ebola and Marburg. The team showed last month that the drug protected cynomolgus macaques against Marburg virus and shielded rodents from Marburg and Ebola virus infections. “We are looking forward to starting a phase 1 clinical trial early next year,” says Sina Bavari, a microbiologist at USAMRIID who is leading the work.

Under the US Food and Drug Administration’s so-called ‘animal rule,’ these experimental treatments for Ebola—for which it would be impractical or unethical to demonstrate efficacy in humans—can be licensed for human use provided that phase 1 trials demonstrate that they are safe in humans. However, aside from Tekmira’s RNAi therapy for Ebola, the phase 1 trial of which is slated to wrap up by the middle of this year, none of these treatments appears likely to clear human safety tests any time soon. “It’s always difficult to see an ongoing outbreak, and we haven’t had time to cross all those tests for licensure,” Kobinger says. But, he adds, “we’re really hoping that we’ll have something in place for the next outbreak.”

Michel Yao (left) and Etienne Minkoulou (right) at the WHO office in Bangui, Central African Republic in March 2014.
{credit}WHO/Christopher Black{/credit}

Armed conflicts and other humanitarian crises are notorious for claiming lives. But any disaster scenario can quickly go from bad to worse when health facilities are abandoned or ransacked. That’s precisely the situation brewing in the Central African Republic, where ongoing political fighting that erupted late in 2012 and intensified last December has plunged the country into chaos and devastated the health system. Many health workers have fled for safety, and looting has damaged health facilities and led to shortages of medicines and other essential supplies.

On 10 April, the United Nations Security Council voted to send peacekeeping forces to the Central African Republic. Meanwhile, the World Health Organization has been collaborating with the country’s Ministry of Health and non-governmental organizations (NGOs) to provide much-needed basic health services in the region. Michel Yao, a physician by training and the senior health security adviser for humanitarian crises at the WHO in Geneva, Switzerland, recently returned from a two-month trip to the Central African Republic. Yao spoke with Nature Medicine about the ongoing medical relief efforts in the beleaguered country.

Can you describe the current situation in the Central African Republic?

There are a huge number of people that are dying—we don’t have an exact number but we’re talking over a thousand people that have lost their lives and several thousand that have been wounded since December. Most of the health facilities have been looted, and health workers also left the health facilities, fleeing to save their own lives. So in this case, the system that is supposed to provide health services to people that are in need cannot work. As an alternative, health care is provided by the humanitarian health workers, but there are few public servants who can still work. The health facilities for the people in the capital city Bangui are more or less covered, but the main challenge remains outside of Bangui.

What are the country’s most pressing health concerns?

Most of the people in the Central African Republic are seeking health services for malaria, diarrheal disease, respiratory infections and vaccine preventable diseases such as measles.

What is the WHO doing to strengthen the health system?

The WHO is trying to focus on a few main areas. The first one is disease surveillance and response to any outbreak. With this early warning system we managed to detect some cases of measles in displacement camps, and we conducted an immunization campaign with our NGO partners to stop the outbreak. The second area is provision of health services, including trauma care, because we have a lot of people who have been wounded in the conflict, which is still ongoing. We are providing medical supplies to some of our NGO partners to make sure that people who are wounded have access to proper treatment, and to treat those diseases that I just mentioned. We are also supporting ambulance services and the blood transfusion center, which are quite critical in terms of trauma treatment.

A polio outbreak occurred last year in Syria, which is also experiencing a humanitarian crisis. Is polio a concern in the Central African Republic?

A few cases of polio were recently confirmed in Cameroon, a neighboring country, so we are concerned about the disease spreading into the Central African Republic due to the low immunization coverage. We are planning to begin a country-wide polio immunization campaign in the Central African Republic towards the end of the month.

How big is your team?

Before the crisis we had about 30 people in our central office in Bangui that has been there almost since the country’s independence. Right now, we have about 50 staff and we have established three sub-offices: one in an area called Bouar, another in Kaga-Bandoro and the last one in Bambari. We have experts in mental health, public health, disease surveillance and data management, all of whom help in terms of planning and designing the response strategy.

How much money is the WHO putting toward this humanitarian response effort?

We are requesting $16 million for our operation, including the deployment of our experts involved in surveillance and planning, and to support coordination with NGOs as well as medical supply equipment. Of this $16 million, right now we have mobilized roughly $4.5 million, or only about 28%. The overall health sector is asking for $56 million, and so far only 21% has been covered. So there is a need to provide more support to the Central African Republic response, assuming that the peacekeeping forces will improve access and will help us to recover the health services.

Take the case of an approach known as DNA-directed RNAi (ddRNAi). In January, Australia-based Benitec Biopharma received a green light from the US Food and Drug Administration to begin the first human trial of an intravenous viral gene therapy based on ddRNAi. The therapy, dubbed TT-034, is essentially a modified form of adeno-associated virus 8, which naturally infects people but is not pathogenic. In TT-034, the viral DNA has been engineered to encode short hairpin RNAs (shRNAs) that silence three different components of the hepatitis C virus (HCV). The approach is referred to ddRNAi because the shRNA that carries out the gene silencing is continually produced by the cell from a DNA vector.

In the trial slated to begin imminently, patients infected with HCV will receive a single injection of TT-034; if it works, it should eliminate the virus from their livers and provide lasting immunity to the disease. Benitec sees it as a potential alternative to existing HCV antiviral therapies, which can involve injections and daily pills for a period of time and can sometimes have debilitating side effects. But some question the need for an RNAi-based HCV therapy. “The available drugs that have just been approved, or will be approved in the next 6 to 12 months, will essentially eliminate the virus from the majority of patients,” says Ralf Bartenschlager, a virologist at Heidelberg University in Germany who studies HCV.

Others worry about whether the vector is optimal for the approach. “I think this concept is something that is going to work,” says Mark Kay, head of the division of human gene therapy at Stanford University in California, and co-founder of Voyager Therapeutics, which launched in February and aims to develop adeno-associated virus-based gene therapies for neurological disorders. “I just don’t think they’re using the right vector. At the time they started, it was the obvious choice. But as more data has accumulated over time, in my opinion, it’s not the right choice.”

That’s in part because recent research using mice with humanized livers suggests that the version of the virus used in TT-034 doesn’t seem to be as effective at infecting human cells as it is animal cells, says Dirk Haussecker, an independent RNAi consultant based in Germany. But David Suhy, senior vice president of research and development at Tacere Therapeutics, a subsidiary of Benitec that originally developed TT-034, says that the humanized mouse models may not accurately represent the architecture and gene expression patterns of human liver, making it unclear whether the virus will actually be less effective in humans compared to mice. “We firmly believe that the best way to see how the TT-034 compound will work in humans is to test it in humans,” he says.

Betting on bifunctionality

Benitec isn’t the only company pursuing the ddRNAi strategy. Gradalis, which is based in Dallas, Texas, is also testing ddRNAi-based therapies in Phase 1 and 2 clinical trials, but has taken a slightly different approach. The company has developed two different types of therapies, both of which impede cancer cells using a so-called bifunctional shRNA design. In this approach, a DNA plasmid produces an RNA that adopts a structure containing two short hairpins—one that is processed by the cell to a small interfering RNA (siRNA) that binds to complementary mRNAs and causes them to be degraded, and another that is processed to a microRNA that binds to the same mRNA target and blocks protein production. “Therefore, you get increased strength of the knockdown, and it lasts longer,” says Charles Brunicardi, a cancer surgeon at the University of California-Los Angeles, who is involved in the clinical and pre-clinical trials of Gradalis’s gene-silencing therapies.

But based on what is now known about the molecular biology of the cellular RNAi machinery, some question the rationale behind the bifunctional approach. That’s because siRNA-mediated gene silencing is faster and more efficient than microRNA-mediated inhibition, says Shuo Gu, a cancer researcher at the US National Cancer Institute in Frederick, Maryland, who studies the molecular mechanisms of RNAi. Therefore, mRNAs that are tied up in microRNA complexes might be less accessible to RNAi cleavage, which would reduce inhibition, he says. “More needs to be known about the mechanisms before we know what we’re dealing with here.”

A third company, Calimmune, which is headquartered in Tucson, Arizona, has licensed the ddRNAi technology from Benitec to develop an experimental anti-HIV agent known as Cal-1, which is currently in phase 1/2a trials. Calimmune’s construct is derived from a lentivirus, which integrates its genetic material into host cells. The therapy delivers an shRNA that knocks down a receptor known as CCR5, which HIV uses to gain access to T cells of the immune system, and also contains the instructions for making a protein known as C46, which blocks HIV’s ability to bind to T cells.

But actually giving the Cal-1 therapy to patients is a complicated process that involves harvesting stem cells from the bone marrow of HIV-infected patients, treating the cells with the therapy in vitro, and then putting the engineered cells back into the patients, who must undergo a ‘conditioning’ process that obliterates much of their immune system so that the engineered stem cells can take hold and repopulate the blood with HIV-resistant cells. “That’s an additional risk and challenge, and there are obvious potential drawbacks in trying to implement that in a large scale way,” says David Margolis, an HIV expert at the University of North Carolina School of Medicine in Durham.

The road ahead

Several companies have already tried their hand at ddRNAi therapies, but with little success. In 2007, the now defunct Pennsylvania-based biotech company Nucleonics prematurely ended its phase 1 trial of a systemic non-viral ddRNAi therapy for hepatitis B virus** after treating only three patients; the drug failed to knockdown its targets and triggered mild immune responses. Similarly, Amsterdam Molecular Therapeutics once pursued viral ddRNAi therapies, but sold its assets to the newly formed biotech company UniQure in late 2012.*** And Pfizer, which partnered with Tacere to develop TT-034, halted it ddRNAi efforts in 2012 and handed the rights to the therapy back to Tacere.

Even if the latest ddRNAi-based therapies turn out to be safe and effective, there’s tough competition from the latest genome-modifying tools, including zinc finger nucleases (ZFNs) and CRISPR, which use DNA cutting enzymes to specifically alter or inactivate genes of interest. For example, California-based Sangamo BioSciences is currently conducting using a ZFN-based approach to delete both copies of the CCR5 gene in the T cells of patients infected with HIV. The modified cells are then expanded in the lab and transplanted back into patients. And just last month, researchers at the Massachusetts Institute of Technology (MIT) in Cambridge reported using CRISPR to cure adult mice of a genetic disorder caused by a single point mutation.

Daniel Anderson, who led the MIT study but has also studied RNAi, says he is personally very optimistic about the therapeutic potential of the gene-editing approaches, although he admits that they have delivery challenges and raise concerns about the potential for off-target genetic modifications. But he acknowledges that there is room for both RNAi and gene-editing forms of gene therapy. “To me, it’s still pretty early to call winners or losers.”

Image by Lightspring via Shutterstock

**Corrections (14 April): An earlier version of this story incorrectly stated that Nucleonics was working on a therapy for hepatitis C virus, but in fact it was hepatitis B virus. ***This story also stated that Amsterdam Molecular Therapeutics folded in 2012, but it is more accurate to say that the company sold its assets to UniQure, which is developing ddRNAi therapies for Huntington’s disease. Nature Medicine regrets the errors.