Dr Giuseppe Ciaramella | Chief Scientific Officer of  Valera

• Giuseppe Ciaramella is the Chief Scientific Officer of Valera LLC, a fully owned venture of Moderna that focuses on the discovery of vaccines and therapeutics for Infectious Diseases using Moderna’s mRNA technology. He joined Moderna in January 2014 as VP of Immunology and Biotherapeutics and was appointed CSO of the newly formed Valera company in October 2014. He has more than 20 years of drug discovery experience at Moderna, Astrazeneca, Boehringer Ingelheim (BI), Pfizer and Merck, and has held several leadership roles, with a particular focus in the fields of antivirals, immunology and biotherapeutics. Prior to joining Moderna, Giuseppe lead the small molecule Antiviral Strategy at AZ. At BI, he was VP and Head of Collaborative Research where he had responsibility for external R&D and was a member of the WW Research Leadership Team. Prior to BI, Pino spent 14 years at Pfizer in the UK where he held several Discovery leadership positions, including Head of Biotherapeutics, Head of Antiviral and Head of Lead Discovery. During his career, Giuseppe has contributed to several clinical candidates, both small molecule and biologics, and to the anti-HIV drug Maraviroc (SelzentryTM), which won the USA Prix Galien for Best Pharmaceutical in 2008. 

• Giuseppe holds a PhD in Biochemistry and Molecular Biology from University College London. He is a Fellow of the Royal Society of Chemistry (UK) and he is a member of the Infectious Diseases Society of America (IDSA).

Giuseppe Ciaramella is the Chief Scientific Officer of Valera LLC, a fully owned venture of Moderna that focuses on the discovery of vaccines and therapeutics for Infectious Diseases using Moderna’s mRNA technology. He joined Moderna in January 2014 as VP of Immunology and Biotherapeutics and was appointed CSO of the newly formed Valera company in October 2014. He has more than 20 years of drug discovery experience at Moderna, Astrazeneca, Boehringer Ingelheim (BI), Pfizer and Merck, and has held several leadership roles, with a particular focus in the fields of antivirals, immunology and biotherapeutics. Prior to joining Moderna, Giuseppe lead the small molecule Antiviral Strategy at AZ. At BI, he was VP and Head of Collaborative Research where he had responsibility for external R&D and was a member of the WW Research Leadership Team. Prior to BI, Pino spent 14 years at Pfizer in the UK where he held several Discovery leadership positions, including Head of Biotherapeutics, Head of Antiviral and Head of Lead Discovery. During his career, Giuseppe has contributed to several clinical candidates, both small molecule and biologics, and to the anti-HIV drug Maraviroc (SelzentryTM), which won the USA Prix Galien for Best Pharmaceutical in 2008.

Giuseppe holds a PhD in Biochemistry and Molecular Biology from University College London. He is a Fellow of the Royal Society of Chemistry (UK) and he is a member of the Infectious Diseases Society of America (IDSA).

Giuseppe Ciaramella, Ph.D., has served as our Chief Scientific Officer since February 2018 and as our President and Chief Scientific Officer since January 2020.

• 1. • Dr. Ciaramella has 25 years of drug discovery experience across different therapeutic modalities, from small molecule, to biologics, to advanced medicinal products, such as mRNA.

     • Prior to joining Beam, Dr. Ciaramella was the Chief Scientific Officer of the Infectious Diseases division of Moderna Therapeutics from 2014 until February 2018, where he was instrumental in generating some of the first LNP-encapsulated, mRNA vaccines to be dosed in humans, several of which are progressing through clinical studies.

     • From 2011 until 2014, Dr. Ciaramella served as Executive Director at Astrazeneca, where he led their small molecule antiviral strategy.

     • Between 2010 and 2011 he served as Vice President and Head of Collaborative Research at Boehringer Ingelheim, where he had responsibility for external research.

     • Prior to Boehringer Ingelheim, he spent 14 years at Pfizer in the U.K. where he held several leadership positions, including head of Biotherapeutics, head of Antivirals and head of the Hit Discovery Group.

     • Dr. Ciaramella is a member of the Infectious Diseases Society of America and of the American Society of Gene Therapy.

     • Dr. Ciaramella holds a Ph.D. in Biochemistry from University College London.

London: In 1996, scientists solved a mystery surrounding certain gay men who were immune to AIDS. This year, Pfizer Inc. will sell the first drug based on that discovery.

The US and European researchers, writing in several science journals, said a small group of Caucasian gay men carry a gene mutation that provides natural protection against HIV, the virus that causes AIDS. This week, culminating an 11-year race among three drugmakers, Pfizer released successful studies of a new pill specifically designed to mimic the gene defect.

“We still remember reading those papers and thinking, ‘God, we should do something with this’," says Pino Ciaramella, a scientist at Pfizer’s laboratories in the UK seacoast town of Sandwich, where the drug was created.

Regulators in Canada, Europe and the US have accelerated reviews of the drug, called maraviroc, based on clinical trials showing that, when combined with other medicines, the pill is more effective than existing therapies in treating AIDS patients. The new drug may gain regulatory approval this year and generate more than $300 million (Rs 1,322 crore) in sales by 2011 for New York-based Pfizer, the world’s largest drugmaker. It also may arm doctors with a new weapon against forms of the virus that are resistant to current treatments.

Ciaramella, 38, says he and his colleagues were spurred into action because the reports involving gay men were followed three months later by another study reinforcing the notion that some people can inherit immunity to HIV. In that research, Canadian and Kenyan investigators reported that 60 prostitutes in Nairobi didn’t become infected after being repeatedly exposed to the virus over 10 years.

As a result of the studies, scientists realized that HIV carries out its damage by first hooking onto a spike called a receptor that juts out from the surface of white blood cells, much as a key enters a lock. The scientists found that the gay men of European descent were shielded from HIV infections by inheriting a defective version of the cell receptor, called CCR5.

Pfizer scientists say this critical finding led them to believe they might be able to create a drug against the virus that worked by binding to the CCR5 receptor, thereby blocking the doorway HIV uses to infect cells.

• PMID: 33186704
•  PMCID: PMC7654230
•  DOI: 10.1016/j.ijid.2020.10.101

“The whole thing was started by noticing this genetic defect," says [Dr Anthony Stephen Fauci (born 1940) ], director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

Other drug companies, including GlaxoSmithKline Plc, based in London, and Schering-Plough Corp. of Kenilworth, New Jersey, also began chasing after their own CCR5-blockers when the gene defect discovery was reported in 1996. Glaxo terminated its project in 2005 when its drug proved to be toxic to the livers of test patients.

Schering-Plough’s candidate suffered a setback in 2006 after five patients in one study developed cancer. The company expects to begin a larger trial of the drug later this year after an independent monitoring board ruled there wasn’t enough evidence to determine the drug caused the cancers, says spokesman Robert Consalvo.

“That’s why competition is good," says David Roblin, Pfizer’s head of clinical research and development at the Sandwich site. “It’s lucky it was us" that succeeded.  Shares of Pfizer rose 8 cents to $25.04 on 1 March in New York Stock Exchange composite trading. The stock has dropped about 4.8% this year.

Maraviroc, when used in combination with other drugs, more effectively suppressed blood levels of the virus than the standard three-drug HIV therapy in current use, according to data Pfizer presented at an AIDS research meeting in Los Angeles on 27 February.

Ciaramella, a biochemist, had only arrived at Pfizer a few months before the 1996 studies were published. “It was one of my first projects," he says.

He and his colleagues spent five months in 1997 at the Sandwich lab, where five of the company’s current 20 top-selling medicines, including Viagra, were discovered.

After finding the chemical with the most promise, the team spent the next two years modifying it. Using robots in a laboratory outfitted to limit the risk of accidental infection, they tinkered with the drug candidate, manipulating its structure to produce more than 1,100 different versions.

By 2000, their research had led to two compounds, maraviroc and another, called UK-436488. The chemicals were structurally identical except a nitrogen bond in the center of the molecules projected outwards in one and inwards in the other.

That difference meant UK-436488 was also 1,000 times less active than maraviroc, says Tony Wood, 41, head of discovery chemistry at the lab. “You can make very small changes and lose activity altogether," he says.

That year, Wood and his colleagues synthesized a prototype drug that tightly experiments in test-tube bound to the CCR5 hook and also appeared unlikely to cause side effects.

“What really made maraviroc stand out was that it was a compound that seemed to balance all the properties we were looking for better than the others," Wood says. “It was very potent."

In the next year, Pfizer tested maraviroc in lab animals including rodents. It was first administered to people in 2001 and, after positive initial results, trials aimed at gaining regulatory approval began at 250 centres in 16 countries in 2004.

Marketing clearance this year would mean that it took about a decade for maraviroc to go from the laboratory to the market. That’s less than the average time of 14.2 years, according to research by Joseph A. DeMasi of the Tufts Center for the Study of Drug Development in Boston.

“That’s faster than most," said Annette Doherty, a Pfizer senior vice president and director of the Sandwich lab.

The US Food and Drug Administration says it will review Pfizer’s application on 24 April and may make its decision in June. The European Medicines Agency may rule on the drug later this year.

One drawback for the drug is that it only works in patients in which HIV uses CCR5 to pierce cells, estimated to be about half the people infected. The virus can use another similar receptor to enter cells of other patients. The drugmaker plans to sell maraviroc only to those patients identified in blood tests as having active CCR5 receptors, company spokesman Joel W Morris says.

The cost of that test may be as high as $1,000 in the US, says Bob Huff, editorial director of New York-based Treatment Action Group, an advocacy group. Pfizer hasn’t set a price for maraviroc. Analysts estimate Pfizer will charge about $5,000 a year for the drug.

Maraviroc may be especially valuable in treating patients for whom existing drugs don’t work anymore. Doctors now estimate that as many as 65,000 people with HIV in the US are resistant to all three major classes of medications and in worsening health.

Blocking the receptor may lead to unintended effects, including the possibility that the virus may eventually find a way into cells through another receptor, say Huff and Fauci. Humans have numerous such receptors, which is why some people can function normally without a working version of CCR5.

“It’s a theoretical risk," says Fauci, “but it’s not so far-fetched either."

CAMBRIDGE, Mass., Jan. 8, 2015 — Moderna Therapeutics, a pioneer in the development of messenger RNA (mRNA) Therapeutics™, today announced the launch of Valera LLC, a new Moderna venture focused exclusively on the advancement of vaccines and therapeutics for the prevention and treatment of viral, bacterial and parasitic infectious diseases. 

The vaccines work of Valera builds on a body of preclinical research at Moderna showing the ability of modified mRNA to express viral antigens in vivo and to induce robust immune responses. Valera’s therapeutic passive immunity programs will expand on Moderna’s research using mRNA to express antibodies that bind to viral and other targets. The robust data from these programs across a range of preclinical infectious disease models, together with the inherent, rapid turn-around time in creating novel mRNA constructs, provide Valera with a potentially powerful and versatile new platform for the creation of a broad array of vaccines and passive immunity therapies.

“We are thrilled to launch Valera to bring sharp focus to developing mRNA Therapeutics for a wide range of infectious diseases, which remain a hugely significant global health threat,” said [Stéphane J. Bancel (born 1972) , president and CEO of Moderna. “We believe that mRNA offers unique advantages when it comes to the rapid design and manufacture of new vaccines and therapies, and we have seen promising signs of efficacy in our preclinical work.”

Mr. Bancel will continue to serve as interim president of Valera. Moderna has engaged the global executive search firm Korn Ferry (NYSE:KFY) to recruit a president for Valera.

[Dr. Giuseppe "Pino" Ciaramella (born 1968)], former vice president and head of immunology and biotherapeutics at Moderna, will serve as chief scientific officer of Valera. Dr. Ciaramella has nearly two decades of global industry experience at AstraZeneca, Boeringher Ingelheim, Pfizer and Merck focused on the discovery and development of small molecule and biological clinical candidates, with a particular focus on antivirals and biotherapeutics. The plan in 2015 is for Dr. Ciaramella to hire and lead a team of 15 scientists to drive early-stage discovery and development at Valera.

Michele Keough, formerly with Moderna’s R&D strategy and operations group, will serve as head of programs and alliance management at Valera. Prior to Moderna, Ms. Keough served as senior director, program and alliance management at Genzyme, a Sanofi company, where she led several of Genzyme’s strategic partnerships with biotechnology companies.

Moderna is actively recruiting for the position of chief medical officer of Valera.

Valera will expand its team significantly in 2015 and will work out of Moderna’s Venture Labs at 320 Bent Street, Cambridge, Mass.

When I describe leading infectious disease research efforts at Moderna, I often say it’s a bit like being a kid in a candy shop. We have this amazing, versatile tool in our hands. And we’re pushing the boundaries of this platform technology’s capabilities by exploring a range of options simultaneously – both across therapeutic areas and within therapeutic areas.     

On the infectious diseases front, our development pipeline currently comprises nine prophylactic vaccines – including monovalent, multivalent and multi-pathogen vaccines. There are Phase 1 studies underway for five of these vaccines. We are advancing several additional prophylactic vaccines as well as antibody programs at the research stage.

Collaborations are an integral part of how we conduct research. Our many academic collaborators and our partners are a critical part of our ecosystem. One of the things we enjoy most is sharing the results of those collaborations with the broader scientific community.

Understanding how our vaccines elicit a robust immune response

I’m quite excited about a paper that we announced today that’s been published in Molecular Therapy in collaboration with Dr. Karin Loré and her team at the Karolinska Institutet. The paper describes the results from a collaboration we undertook with Dr. Loré to gain a firmer understanding of the kinetics of our vaccines – how they’re absorbed and distributed – as well as how they interact with specific cells of the immune system.   

We embarked on this collaboration a couple of years ago, compelled by a growing body of strong preclinical data. In animal models, our vaccines were eliciting a robust immune response, and we wanted to understand mechanistically how they were working.

This study was conducted in non-human primates (NHPs) to closely reflect what happens in humans.  For one part of this study, we selected a research version of our influenza H10N8 vaccine, which we were already planning to take to the clinic.

(Read here about the human data we published for our H10 vaccine in April 2017.)

Our vaccines, including H10N8, are composed of lipid nanoparticle (LNP)-encapsulated mRNAs. For this study, we also made another vaccine where we labeled the LNP with a fluorescent molecule. And then the mRNA we used coded for a reporter protein, which would create a fluorescent signal different from the fluorescent molecule we used on the LNP.

Once we injected the vaccine, we could then follow both where the LNP went and where the mRNA went, as a consequence of the protein being expressed. 

What we found

The H10N8 vaccine elicited a robust immune response, and we confirmed both antibody and T cell responses. We were also able to characterize the antibody response in terms of quality and timing.

Following administration of the vaccine in the muscle, we saw antigenic expression in macrophages (a type of white blood cell) at the injection site.

The vaccine then drained to the lymph nodes closest to the injection site, as would be expected for any vaccine.  Importantly, though, the vaccine was also taken up by dendritic cells in the lymph nodes, and we saw antigenic protein expression in these cells as well. 

We also were able to characterize the various subsets of immune cells that were actually interacting with the vaccine – taking it up and expressing it.

Key takeaways … and significance of findings at the platform level

With these findings, we now have preclinical data demonstrating that our H10N8 vaccine is draining into the lymph nodes, and we also know exactly where in the lymph nodes. And we’ve confirmed that the vaccine is expressing antigenic proteins both at the injection site as well as in antigen-presenting cells (dendritic cells) in the lymph nodes. We believe it is the combination of these two that is responsible for the robust immune response we’re seeing from our vaccines.

Importantly, given the software-like nature of our medicines, these results should be, in the main, consistent across our other vaccines.

We’re grateful that we had the opportunity to work with Dr. Loré and her colleagues to help us better characterize the immune response to our vaccines.

And we’re excited to share more about our progress in development in the months ahead.

Moderna Therapeutics, a private biotech firm worth a reported $7.5 billion, lost its head of vaccines just after the company raised $500 million on the promise of advancing vaccines into late-stage trials.

Giuseppe Ciaramella, who joined Moderna in 2014, left the company in February for a job at an early-stage biotech startup, according to people familiar with the matter. As chief scientific officer of Moderna’s vaccine business, Ciaramella managed the company’s most-advanced projects, authoring the firm’s journal publications and shepherding seven investigational vaccines into clinical trials.

It was Ciaramella who first suggested that Moderna’s foundational technology could be useful in vaccines, former employees said, an idea that became vitally important to the company when it pivoted to infectious disease after repeated setbacks to its ambitions in rare disease.

Ciaramella, who goes by Pino, “was a valued contributor and colleague, leading infectious disease discovery for many years, and we wish him all the best in his new role,” Moderna spokesman Jason Glashow said in a statement. “Our vaccine programs remain on track in the clinic and a high strategic priority for the company. We have remarkably strong leadership in our vaccine unit, and we remain excited in the strength of the portfolio.”

Ciaramella did not immediately respond to a request for comment.

His departure is the latest in a long string of high-profile exits at Moderna. In October, the company lost its head of chemistry, the leader of its cardiovascular division, and the head of its rare disease division, who was hired to replace an executive who quit in 2016. Months before, Moderna parted ways with the head of its cancer business, its chief business officer, and its lead attorney, who took another job in the middle of a contentious dispute over patents.

Meanwhile, Moderna is pressing forward with a $500 million new funding round, disclosed last month. Fundraising took the better part of a year, according to people familiar with the matter, as Moderna struggled to convince some investors to back its lofty valuation. The cash comes from an investor syndicate uncommon in biotech, including the sovereign wealth fund of Abu Dhabi, the investment arm of the Singapore Economic Development Board, and Sequoia Capital China. 

What if a single injection could lower blood levels of cholesterol and triglycerides — for a lifetime?

In the first gene-editing experiment of its kind, scientists have disabled two genes in monkeys that raise the risk for heart disease. Humans carry the genes as well, and the experiment has raised hopes that a leading killer may one day be tamed.

“This could be the cure for heart disease,” said Dr. Michael Davidson, director of the Lipid Clinic at the University of Chicago Pritzker School of Medicine, who was not involved in the research.

But it will be years before human trials can begin, and gene-editing technology so far has a mixed tracked record. It is much too early to know whether the strategy will be safe and effective in humans; even the monkeys must be monitored for side effects or other treatment failures for some time to come.

The results were presented on Saturday at the annual meeting of the International Society for Stem Cell Research, this year held virtually with about 3,700 attendees around the world. The scientists are writing up their findings, which have not yet been peer-reviewed or published.

The researchers set out to block two genes: PCSK9, which helps regulate levels of LDL cholesterol; and ANGPTL3, part of the system regulating triglyceride, a type of blood fat. Both genes are active in the liver, which is where cholesterol and triglycerides are produced. People who inherit mutations that destroyed the genes’ function do not get heart disease.

People with increased blood levels of triglycerides and LDL cholesterol have dramatically greater risks of heart disease, heart attacks and strokes, the leading causes of death in most of the developed world. Drug companies already have developed and are marketing two so-called PCSK9 inhibitors that markedly lower LDL cholesterol, but they are expensive and must be injected every few weeks.

Researchers at Verve Therapeutics, led by Dr. Sekar Kathiresan, the chief executive, decided to edit the genes instead. The medicine they developed consists of two pieces of RNA — a gene editor and a tiny guide that directs the editor to a single sequence of 23 letters of human DNA among the genome’s 3.25 billion so-called base pairs.

The RNA is shrouded in tiny lipid spheres to protect the medicine from being instantly degraded in the blood. The lipid spheres travel directly to the liver where they are ingested by liver cells. The contents of the spheres are released, and once the editor lands on its target, it changes a single letter of the sequence to another — like a pencil erasing one letter and writing in another.

Not only did the system work in 13 monkeys, the researchers reported, but it appeared that every liver cell was edited. After gene editing, the monkeys’ LDL levels dropped by 59 percent within two weeks. The ANGPTL3 gene editing led to a 64 percent decline in triglyceride levels.

One danger of gene editing is the process may result in modification of DNA that scientists are not expecting. “You will never be able to have no off-target effects,” warned Dr. Deepak Srivastava, president of the Gladstone Institutes in San Francisco.

In treating a condition as common as heart disease, he added, even an uncommon side effect can mean many patients are affected. So far, however, the researchers say that they have not seen any inadvertent editing of other genes.

Another question is how long the effect on cholesterol and triglyceride levels will last, Dr. Davidson said. “We hope it will be one-and-done, but we have to validate that with clinical trials,” he said.

Jennifer Doudna, a biochemist of the University of California, Berkeley, and a discoverer of Crispr, the revolutionary gene editing system, said: “In principle, Verve’s approach could be better because it’s a one-time treatment.”  But it is much too soon to say if it will be safe and long-lasting, she added.

If the strategy does work in humans, its greatest impact may be in poorer countries that cannot afford expensive injections for people at high risk of heart disease, said Dr. Daniel Rader, chairman of the department of genetics at the University of Pennsylvania and a member of Verve’s scientific advisory board.

Dr. Kathiresan, of Verve, noted that half of all first heart attacks end in sudden death, making it imperative to protect those at high risk.

Dr. Kathiresan began the research at the Massachusetts General Hospital and the Broad Institute, where he and his colleagues found a collection of genes that increase risk of heart attack at a relatively young age, as well as eight genes that, when mutated, decrease risk.

Those protective genes, he reasoned, could be targets for gene editing if there were a way to alter them in people. Gene editing is only now succeeding, and so far its successes have been in rare diseases.

Other investigators and companies have tried editing genes in mice to prevent heart disease, with some success, but primates are a much more difficult challenge.

Dr. Kathiresan said that to his knowledge, his study is the first to use the pencil-and-eraser type gene editing in primates for a very common disease. Verve licensed the technology, called base editing, from Beam Therapeutics.

If all goes well, Dr. Kathiresan hopes in a few years to begin treating people who have had heart attacks and still have perilously high cholesterol. For them, the risk of another heart attack is so high that the possible benefit may far outweigh the risks of the treatment.

Heart disease generally occurs only after decades of high cholesterol levels, Dr. Davidson noted. By age 50, people most likely to have a heart attack already have a significant accumulation of plaque in their arteries.

But if the PCSK9 gene could be knocked out in 20-year-olds, he said, “there would be no heart disease in their future.”

Dewpoint Therapeutics announced Tuesday that it has raised $77 million in its second round of venture funding, which will help the company continue to target “undruggable” diseases through an emerging field in cell biology.

The Boston-based biotech works on organelles inside cells called biomolecular condensates, which it believes can be harnessed to treat diseases including cancer and rare genetic disorders. Condensates are membrane-less droplets that help cells perform vital functions.

The funding round was led by Chicago-based ARCH Venture Partners, bringing Dewpoint’s total venture financing to $147 million. The deal attracted new investors Maverick Ventures and Bellco Capital, and previous investors Leaps by Bayer, EcoR1 Capital, Polaris Partners, Samsara BioCapital, and Innovation Endeavors also participated in the round.

“Today’s announcement underscores the interest in biomolecular condensates among investors with a track record of backing groundbreaking science," Amir Nashat, managing partner of Polaris Partners and interim chief executive of Dewpoint, said in a news release.

Since its founding in 2018, Dewpoint has signed deals with two pharmaceutical giants. In July, Dewpoint announced a collaboration with Merck & Co. to work on the treatment of HIV, and in November, Dewpoint announced it would work with German pharmaceutical company Bayer to develop new treatments for cardiovascular and gynecological diseases.

Dewpoint also announced Tuesday that Giuseppe Ciaramella, the president and chief scientific officer of Beam Therapeutics, would join its board of directors. Prior to Beam, Ciaramella worked at Moderna in Cambridge, first as head of immunology and biotherapeutics and then as chief scientific officer of its infectious diseases division.

 On August 28, 2020, KEI asked DARPA to investigate apparent failures to disclose U.S. government funding into Moderna’s patents and applications. The request, which was first covered by the Washington Post, and subsequently by Statnews, Law360, the Financial Times and Bloomberg, stems from our analysis of DARPA support for Moderna’s mRNA vaccine research since 2013. The KEI report examined in particular 11 patents where DARPA funding appears to have been relevant, given the subject matter, inventors and published papers linking the research to DARPA grants.

On August 29, 2020, DARPA spokesman Jared Adams gave these comments to the Financial Times:

• “It appears that all past and present Darpa awards to Moderna include the requirement to report the role of government-funding for related inventions,” Darpa spokesman Jared Adams said in an emailed response to the Financial Times.

• “Further, Darpa is actively researching agency awards to Moderna to identify which patents and pending patents, if any at all, may be associated with Darpa support,” he said.

• Mr Adams declined to comment further, saying the investigation was continuing. US federal law required government funding to be disclosed in these circumstances, he noted.

Bloomberg reported on the FT report regarding the DARPA investigation, but added the statement “at least one Darpa-linked patent shows government support was disclosed” and Moderna has made this claim to the FT after its original story was published.

KEI’s research into Moderna failures to disclose DARPA funding involved an examination of 126 patents granted by USPTO and 154 patent applications published by USPTO.

Moderna appears to be referring to a single Moderna international application made to the World International Property Organization, which manages the Patent Cooperation Treaty (PCT). This international application – WO2019136241A1 – acknowledged support from the DARPA awards, is directed to Chikungunya antibodies and also lists Vanderbilt University as one of the applicants.

WO2019136241A1 was not one of the documents we surveyed since it is an international PCT procedure and not a published U.S. application. The Bayh-Dole disclosure requirements apply to patents filed in the United States. Nonetheless, the fact that this PCT application makes a disclosure is interesting, particularly since WO2019136241A1 names Giuseppe Ciaramella and Sunny Himansu as two of the co-inventors, two scientists who have acknowledged performing work under the DARPA awards, and who also appear as co-inventors in several of Moderna’s USPTO patents and applications where KEI has asked DARPA to investigate Moderna’s failure to disclose DARPA funding.

Messenger RNA (mRNA) is having a moment. This year, hundreds of millions of people will receive shots of the Pfizer-BioNTech or Moderna vaccines for COVID-19. The crucial ingredient in each injection is mRNA, short-lived strands of genetic material that prompt our cells to start making SARS-CoV-2 proteins, which in turn help our immune systems develop antibodies that prevent future infections. Thanks to decades of scientific perseverance, billions of dollars of investment in the technology, and previous work on coronaviruses, the vaccine makers were able to design their vaccines and prove their safety and efficacy in under a year.

The success of these COVID-19 vaccines is remarkable and was far from guaranteed. mRNA is incredibly delicate. Enzymes in the environment and in our bodies are quick to chop mRNA into pieces, making lab experiments difficult and the delivery of mRNA to our cells daunting. On top of that, mRNA strands are large and negatively charged and can’t simply waltz across the protective lipid membranes of cells. Many scientists thought the technology would never work.

“There were many, many skeptics,” says Frank DeRosa, who began working with mRNA in 2008 and is now chief technology officer at Translate Bio, a firm developing mRNA vaccines with Sanofi. “People used to say that if you looked at it wrong it would fall apart.”

Luckily, scientists found a solution. To protect the fragile molecule as it sneaks into cells, they turned to a delivery technology with origins older than the idea of mRNA therapy itself: tiny balls of fat called lipid nanoparticles, or LNPs.

LNPs used in the COVID-19 vaccines contain just four ingredients: ionizable lipids whose positive charges bind to the negatively charged backbone of mRNA, pegylated lipids that help stabilize the particle, and phospholipids and cholesterol molecules that contribute to the particle’s structure. Thousands of these four components encapsulate mRNA, shield it from destructive enzymes, and shuttle it into cells, where the mRNA is unloaded and used to make proteins. Although the concept seems simple, perfecting it was far from straightforward.

Over more than 3 decades, promising lipids studied in the lab often failed to live up to their potential when tested in animals or humans. Positively charged lipids are inherently toxic, and companies struggled for years before landing on formulations that were safe and effective. When injected intravenously, the particles invariably accumulated in the liver, and delivery to other organs is still an obstacle. Reliably manufacturing consistent LNPs was another challenge, and producing the raw materials needed to make the particles is a limiting factor in the production of COVID-19 vaccines today.

LNP development has been a headache, but without this packaging, mRNA vaccines would be nothing. “It is the unsung hero of the whole thing,” says Giuseppe Ciaramella, who was head of infectious diseases at Moderna from 2014 to 2018.

The vaccines, appropriately celebrated as a first for mRNA technology, are also a milestone for the nanoparticle field. Although the first drug based on an LNP was approved by the US Food and Drug Administration for a rare genetic disease in 2018, the two authorized mRNA vaccines for COVID-19 present a far bigger opportunity for the nanoparticles than even the field’s founders can imagine. “It is a tremendous vindication for everyone working in controlled drug delivery,” says Robert Langer, a chemical engineer at the Massachusetts Institute of Technology.

“LNPs will be going into millions of arms over the course of this year,” says University of British Columbia nanoparticle scientist Pieter Cullis. “What was a fringe field back in the 1980s has turned into something that is mainstream now.”

The delivery dilemma

Modern LNPs can be traced back to work on simpler systems called liposomes, hollow lipid spheres often made of just two or three kinds of lipids. In the early 1980s, Cullis found that cancer drugs could diffuse into these liposomes and get trapped in the hollow core. When injected into animals with cancer, the liposomes would slip through the leaky vasculature of tumors, enter cells, and unleash a drug. Cullis, and several others, started companies with the hope that liposomes could safely deliver otherwise toxic drugs into tumors in humans.

Progress was slowed by issues with stability and manufacturing. The first liposome-based drug eventually was approved by the FDA in 1995, but by then Cullis and many in the field had moved on to a new challenge: using lipid particles to deliver nucleic acids such as DNA and RNA.

"The devil is absolutely in the details as far as LNPs are concerned." ..  Giuseppe Ciaramella, former head of infectious diseases, Moderna

At the time, scientists were enamored by advances in genetics that were promising to cure diseases by giving someone new genes or turning disease-causing genes off. Figuring out how to deliver these nucleic acid therapies—either DNA or RNA—into cells was a major challenge and required something more sophisticated than a conventional liposome. Cullis knew that adding positively charged lipids to the liposomes would help balance the negatively charged nucleic acids, but there was a problem. “There are no cationic lipids in nature,” Cullis says. “And we knew we couldn’t use permanently positively charged lipids because they are so damn toxic.” Those lipids would rip cell membranes apart, he adds.

A solution came from new lipids that were charged only under certain conditions. During the late ’90s and through the first decade of the 2000s, Cullis, his colleagues at Inex Pharmaceuticals, and the Inex spin-off Protiva Biotherapeutics developed ionizable lipids that are positively charged at an acidic pH but neutral in the blood. The group also created a new way to manufacture nanoparticles with these lipids, using microfluidics to mix lipids dissolved in ethanol with nucleic acids dissolved in an acidic buffer. When the streams of those two solutions merged, the components spontaneously formed lipid nanoparticles, which, unlike the hollow liposomes, were densely packed with lipids and nucleic acids. The process was simple in theory, but getting the machine to reliably spit out consistent LNPs was difficult.

LNPs that looked good in the lab often floundered in the clinic, however. The first versions of ionizable lipids were still toxic. And early formulations of the nanoparticles didn’t degrade fast enough, causing them to accumulate after repeated injections. Protiva found that one of its experimental LNP therapies caused a more severe immune reaction in humans than it had in the lab, and the company pinned pegylated lipids as a major factor.

Pegylated lipids, in which polyethylene glycol (PEG) strands are attached to lipid heads, have several functions in a nanoparticle. PEG helps control the particle size during formulation, prevents the particles from aggregating in storage, and initially shields the particles from being detected by immune system proteins in the body, according to James Heyes, a former Protiva scientist. Heyes is now chief scientific officer of the LNP company Genevant Sciences—a firm with origins in Protiva.

But PEG also has liabilities. It prevents LNPs from binding to proteins that help shuttle them into cells. Because PEG extends particles’ life span in the body, the immune system has more time to spot the particles and start mounting an antibody response. And although PEG is found in many cosmetic, drug, and food products, scientists hypothesize that some people could develop antibodies to PEG and that giving those individuals an injection of PEG-coated nanoparticles could trigger an anaphylactic reaction.

Escape from the endosome

By 2005, the development of better and safer LNPs was driven by excitement for a new technology, called small interfering RNA (siRNA), for selectively silencing genes. Alnylam Pharmaceuticals, which became the leading siRNA company, quickly realized that existing nanoparticles were not very good at helping siRNA get into cells. The company struck multiple partnerships to make new LNPs, including with Protiva in 2005 and Inex in 2006. The groups made more than 300 ionizable lipids, first optimizing the fatty tails, then tweaking the ionizable head group and the linker region in between. The work was grueling, and lipids that made great nanoparticles in a petri dish would often flop in animal studies. “You can have 50 different ionizable lipids that all deliver effectively to cells in culture, and 49 of them won’t work a damn in vivo,” recalls Thomas Madden, who worked at Inex and is now CEO of Acuitas Therapeutics.

LNPs take advantage of a natural process called receptor-mediated endocytosis to get into cells, Madden explains. Upon binding to a cell, the nanoparticle becomes encapsulated in an even bigger lipid bubble—an organelle called an endosome. The endosome’s acidic interior protonates the heads of the ionizable lipids, making them positively charged. That positive charge triggers a change in the shape of the nanoparticle, which scientists think helps it break free from the endosome and ultimately release its RNA cargo into the cell’s cytoplasm. Once released, the RNA is free to do its job.

The most effective nanoparticles were ones that the body mistook as low-density lipoprotein (LDL) cholesterol—commonly called bad cholesterol. Proteins that recognize LDL cholesterol in the blood bound to some of Alnylam’s nanoparticles and carried them to LDL receptors on liver cells, which then caused the cells to engulf the nanoparticles in an endosome. It was the kind of complex interplay that studies in a petri dish missed.

“A lot of work has gone into studying what happens inside a cell, but trying to understand the transport that occurs before these nanoparticles reach their cells is another question entirely,” says Kathryn Whitehead, a nanoparticle scientist at Carnegie Mellon University. As a consequence, “we don’t even screen in vitro anymore,” she says. “I find it more informative to test directly in an animal.”

Even some of the LNPs that worked well in animals proved too toxic for the repeated dosing required of many siRNA therapies. “The biggest issue was trying to find the right balance between systems that were effective but also safe and tolerable,” says Marian Gindy, executive director of pharmaceutical sciences at Merck & Co., who led the RNA formulation team from 2008 until Merck ended its siRNA programs in 2013. “And I would say that is still the biggest challenge in this area.”

By 2010, Alnylam had landed on a winning ionizable lipid known as MC3. Nanoparticles based on MC3 required about one-thousandth the dose of LNPs made using older ionizable lipids. Alnylam used the new formulation in patisiran (Onpattro), its treatment for a rare disease called hereditary transthyretin-mediated amyloidosis. In 2018, patisiran became the first approved siRNA drug and the first approved therapy delivered via LNPs. But the drug requires an 80 min infusion every 3 weeks and pretreatment with multiple anti-inflammatory drugs to minimize reactions to the nanoparticle. By the time patisiran was showing promise in the clinic, Alnylam had set most of its LNP work aside in favor of a new chemical conjugation technology that it used to deliver its other siRNA therapies subcutaneously.

A launchpad for mRNA

For a brief time, new work on LNPs fell out of favor—that is, until new companies that were focused on mRNA brought fresh energy to the field. BioNTech, founded in 2008, and Moderna, founded in 2010, promised to be able to use mRNA to produce any protein in the body, as either a therapeutic or a vaccine. In the past decade, mRNA garnered billions of dollars of investment. Discovering how to deliver those mRNA strands into cells was a problem from day 1, but prior experience with siRNA provided a launching pad.

“Early on people recognized that the same lipids used for siRNA could also be useful for mRNA,” says Daniel Anderson, a nanomedicine and biomaterials scientist at MIT. His group began collaborating with the rare-disease company Shire Pharmaceuticals to encapsulate mRNA that encoded protein therapies to treat rare liver diseases.

The off-the-shelf LNP formulations designed for siRNA worked for mRNA occasionally but not very well, says Romesh Subramanian, who led a team at Alexion Pharmaceuticals that worked on mRNA therapies with Moderna from 2014 to 2017. siRNA molecules are like short rods, with two rows of about 20 nucleotides each, he explains. mRNA, in contrast, can easily span thousands of nucleotides, wind into complex shapes, and change the properties of the LNP in ways that are hard to predict.

After realizing that MC3 wouldn’t cut it for mRNA delivery, Moderna invested significant resources into building a better ionizable lipid. “There was a group of chemists put on this right away to build novel cationic lipids,” says Ciaramella, the former head of infectious diseases at Moderna. “It is kind of like a small-molecule drug discovery engine, but on steroids.” The team made about 100 ionizable lipids and introduced ester linkages into the carbon chains of the lipids to help make them more biodegradable, he recalls. Tweaking the ratio of the four lipids in the nanoparticles altered the LNPs’ distribution in the body. “The devil is absolutely in the details as far as LNPs are concerned,” Ciaramella says. “But once you optimize it for one organ, you can change out the mRNA with minimal optimization.”

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That adaptability is key. For example, Moderna recently made an updated version of its COVID-19 vaccine for a new variant of the coronavirus first identified in South Africa. In that vaccine, which must still undergo clinical testing, the mRNA code is slightly changed to match the genetic code of the new strain of the virus, but the LNP formulation remains the same. Now that the company knows its nanoparticle works, it can use it over and over again for different vaccines.

But details on how Moderna arrived at its optimal formulation in the first place are scant. The company did not grant an interview to talk about its nanoparticle development, and neither did Pfizer or BioNTech. For its COVID-19 vaccine, Moderna ultimately used an ionizable lipid that it calls SM-102, which it first described in a 2018 study on alternatives to MC3. Pfizer and BioNTech licensed an ionizable lipid called ALC-0315 from Acuitas.

Those ionizable lipids, which are remarkably similar in structure, were discovered while the firms were optimizing LNPs for systemic administration and delivery to the liver—not the intramuscular injection of a vaccine. Experts point out that optimizing the nanoparticles for vaccination could lead to shots that require lower doses, which could ease the manufacturing burden amid a pandemic. New lipids and nanoparticle formulations will likely take too long to develop to make a difference during this pandemic, but Moderna, BioNTech, and others are continuing to look for better ways to get mRNA into cells for a variety of applications.

An LNP resurgence

The pandemic has reinvigorated interest in continuing to refine LNPs. Small firms dedicated to the nanoparticles are getting more calls from larger drug companies that want to use their lipids. Effective LNPs could be crucial for new mRNA vaccines, mRNA therapies, DNA gene therapies, and even CRISPR gene-editing thrapies.

“Everyone is trying to figure out the next big ionizable lipid,” says Gaurav Sahay, a nanoparticle scientist at Oregon State University.. But he thinks that nanoparticle researchers should also start paying more attention to the other components of an LNP. Sahay says his lab found that using alternative versions of cholesterol molecules could dramatically improve delivery. And although both the Moderna and Pfizer-BioNTech vaccines use the same standard phospholipid, swapping out this ingredient for a different phospholipid could lead to nanoparticles that reach different cells in the body, Whitehead says.

“Delivery into specific cell and tissue populations is still a huge challenge for the field,” says Yizhou Dong, a nanoparticle researcher at the Ohio State University. Right now, intravenous injections of nanoparticles can easily reach the liver, and intramuscular injections for vaccines are taken up by immune cells. Some companies are working on experimental formulations for aerosolized delivery to the lungs, but the rest of the body remains out of reach, and the demand for targeted delivery is high. In late February, the CRISPR base-editing company Beam Therapeutics, where Ciaramella is president and chief scientific officer, paid $120 million to acquire the start-up Guide Therapeutics, which is focused on LNP discovery and has a system for finding particles that target specific cells of the body.

“There was this time when LNPs went through the dark ages,” says Thomas Barnes, CEO of the mRNA company Orna Therapeutics. “I think there is going to be a bit of a renaissance in these ionizable lipids and that the world is going to get excited about LNPs again.”

For now, the success of the COVID-19 vaccines is a sweet victory. “It is a little surreal, honestly,” Anderson says. “It is something that we went from just being excited about to something that my mom got in a shot in January.”

Last summer, Pfizer disclosed its long-term strategy to continue using messenger RNA, the key ingredient in its blockbuster COVID-19 vaccine, to treat other diseases.

The company said it wanted to explore how mRNA could be used to edit the human genome, and hinted that it would pursue an approach called “base editing.” The goal of base editing is to precisely — and permanently — change a single letter of DNA to cure a disease.

It didn’t take long for Cambridge biotech Beam Therapeutics, which is pioneering base editing, to get a call from the New York pharmaceutical giant.

The companies said Monday they are partnering to work on genetic medicines for three undisclosed diseases involving the liver, muscles, and central nervous system. Pfizer will pay Beam $300 million upfront in the biotech startup’s largest collaboration to date.

“Pfizer was looking for what’s next,” said Beam chief executive John Evans. “[Messenger RNA] is transient, so you want to have a permanent impact on the body. One way to do that is with a vaccine and another way is with a gene edit.”

In the COVID-19 vaccines, mRNA teaches the body to make the spike protein of the virus to trigger an immune response, and it is delivered through lipid nanoparticles. (The COVID vaccines do not alter a person’s DNA.)

Evans said in other applications, mRNA could be used to carry information for a so-called “base editor,” which would permanently change a letter in a person’s genome to cure a disease. Lipid nanoparticles are known to reach the liver, but Beam is working on delivering genetic therapies to other organs, muscles, and the central nervous system.

Base editing is thought to overcome the challenges associated with traditional gene-editing methods, since it would be more precise and efficient.

“This could be a very disruptive and exciting transition in medicine . . . moving toward a one-time, curative therapy,” he said.

Giuseppe Ciaramella, the president and chief scientific officer of Beam, said a focus on gene editing with mRNA is an “obvious” move for Pfizer, given its experience with developing and manufacturing its COVID-19 vaccine. This is an area Ciaramella knows particularly well; before Beam, he worked on vaccines at Moderna.

As part of the deal, Pfizer can develop and commercialize the three candidates that Beam discovers, and Beam can choose to co-develop and market one of them. Beam is eligible for an additional $1.05 billion in regulatory, commercial, and milestone payments if all programs pan out.

“It’s a transformational deal . . . a great sign of validation,” Evans said.

Evans said Beam plans to accelerate its hiring plans for 2022 because of the deal. Since last December, the company has grown from 180 employees to more than 300.

Founded in 2017, Beam raised $180 million in an initial public offering in February 2020. The company’s base-editing technology was developed by David Liu, a researcher at the Broad Institute of MIT and Harvard, who has founded several local biotechs. 

The announcement came just ahead of the first day of the J.P. Morgan Healthcare Conference, which pivoted to a virtual event because of the Omicron variant.

Evans said this year’s format will be more “efficient” than in years past.

“It’s fun to be in a crowded hallway in a hotel in San Francisco sometimes, but I think this sort of event works virtually,” Evans said.