While ReCode Therapeutics moves toward human trials for its lead programs in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) over the next year, the company is already looking ahead to expanding its pipeline beyond treating respiratory disorders through a recently completed Series B round.
The expanded Series B adds $120 million to the $80 million that ReCode raised in its initial second round last fall. More importantly, the additional financing brings with it more big-name biopharma investors, as the venture capital arms of Bayer and Amgen join those of Pfizer and Sanofi as backers of the company.
“The reason we went back to expand on our B round was to expand and diversify the potential of this platform to new tissue types and new forms of genetic medicines,” ReCode CEO Shehnaaz Suliman, MD, MPhil, told GEN Edge.
“With this fundraising, we now have the ability to target additional tissues, such as the central nervous system and oncology. These allow us to really maximize the potential of this differentiated platform, while at the same time enabling us to get into the clinic with our lead programs.”
The expanded Series B brings ReCode’s total capital raised to $280 million—enough to extend the company’s capital runway another year to the end of 2024. ReCode said the new proceeds will enable it to fund pipeline expansion into as-yet-unspecified central nervous system (CNS), liver, and oncology indications.
The funding will also allow ReCode to advance its PCD and CF programs into the clinic, and further develop its genetic medicine delivery platform to deliver additional treatments—from gene correction modalities and small interfering RNA (siRNA) therapies—to a wider range of target cell types both predictably and programmable.
The financing will also enable ReCode’s planned expansion from a space shared with five other startups to its own 30,000-square-foot facility in Menlo Park, CA, where the company is based, as well as the company’s workforce, which will grow from about 70 people at present to about 100 by year’s end.
A June 10 report by McKinsey & Co. projected that more than 400 RNA-based therapies in development phases will require targeted delivery mechanisms—yet companies specializing in LNP delivery had seen up to that time “relatively small” funding rounds of around $25 million each, around half of the $45 million average deal size for drug delivery companies.
Five lipid approach
ReCode develops genetic medicines based on its own selective organ targeting (SORT) delivery platform—a platform of LNPs designed to deliver treatments with precision, as well as safely and effectively. SORT LNP is an approach to tissue-specific mRNA delivery and gene editing in which LNPs are systematically engineered to exclusively edit extrahepatic tissues and therapeutically relevant cell types.
ReCode licenses SORT LNP technology from the Texas laboratory of Daniel J. Siegwart, PhD, a co-founder of ReCode and scientific advisor to the company. His lab reported the first non-viral system for in vivo CRISPR-Cas gene editing in December 2016. (Siegwart is the W. Ray Wallace Distinguished Chair in Molecular Oncology Research at the University of Texas Southwestern Medical Center, where he is also Director of the Program in Genetic Drug Engineering, Director of the Drug Delivery Program in the Department of Biochemistry, Department of Biomedical Engineering (BME), and Co-leader of the Chemistry and Cancer Program at the Simmons Comprehensive Cancer Center.)
“The current data disclosing the high degree of editing in specific cells positions the discovery of SORT LNPs to treat an array of diseases in a highly accurate manner… SORT may open new avenues of development for gene correction therapeutics,” Siegwart and colleagues concluded in a 2020 study detailing SORT LNP, published in Nature Nanotechnology.
While traditional, first-generation LNPs consist of four lipids and are primarily taken up by the low-density lipoprotein (LDL) receptor in the liver, limiting their usefulness for broad therapeutic applications, SORT LNPs are engineered with five lipids. The fifth is biochemically distinct from the others, which changes how the lipids interact with proteins inside the body—which in turn enables the lipids to be directed and delivered directly to different tissues, organs, and cell types beyond the liver.
“Ours is a five-component system, and the last one can be our choice of lipid,” Angele Maki, PhD, senior vice president and head of business development at ReCode, told GEN earlier this year.
By choosing whether to use an ionizable or charged lipid, Maki said, users of SORT LNP can target the lungs, spleen, or other organs beyond the liver.
“Not only can we go to organs of interest, but we can go to specific cell types of interest within those organs,” Suliman said. “This is really a game changer because it means, for example, in the case of a CF patient that is unable to manufacture CFTR protein, that we can deliver the CFTR protein directly via an inhaled formulation into the secretory cells that lack of protein, and show that we’re able to upregulate protein expression by doing that.”
Genetic medicine “cargoes” can be delivered by messenger RNA (mRNA), silent RNA (siRNA), or gene correction modalities. Delivery is even potentially possible with DNA, something precluded when delivery occurs via viral vectors.
“With viral delivery, you rely on HeLa and AGK [acylglycerol kinase], mammalian cell cultures that need to be expanded, that are very expensive that are not really scalable,” Suliman explained. “But non-viral delivery is a synthetic chemical production methodology—there’s just chemistry, not as much biology, and cell culture. This means you can scale up significantly, as has been done with the COVID vaccines, do redosing, keep the cost of goods down. These are just some of the significant advantages that non-viral delivery platforms, such as LNPs have.”
Direct delivery, ReCode reasons, offers improved efficacy and potency over viral delivery methods, while limiting potential adverse effects.
“It was a very clever breakthrough, to be able to move beyond the box that the traditional four-component LNP field was in,” recalled David Lockhart, PhD, ReCode’s President and Chief Scientific Officer.
Speaking with GEN Edge last year, Lockhart said, “We chose the LNPs because they are a purely chemical approach. The components can be made with well-defined scalable chemistry. There are no peptide components, no viruses, and nothing that requires a bioreactor.”
ReCode says its use of LNPs has been borne out by the success of the messenger RNA (mRNA)-based COVID-19 vaccines developed by Pfizer and BioNTech as well as by Moderna.
Recode’s pipeline is anchored by preclinical inhaled and IV lead programs for CF caused by nonsense mutations, as well as an inhaled treatment for PCD. The CF treatment focuses specifically on the 10–13% of patients who have nonsense mutations that cannot fully benefit from current small molecule therapies.
At the American Thoracic Society (ATS) 2022 International Conference, held in May in San Francisco, ReCode presented positive preclinical data for both programs. The data showed that both the PCD and CF candidates can be precisely delivered directly to disease-relevant cells without significant exposure to other tissue, effectively releasing the encapsulated genetic cargo, and expressing the correct proteins at relevant levels.
“We’ll file the IND for primary ciliary dyskinesia in Q4 of this year, which means that we expect to be enrolling patients in Q1 next year. And the IND filing for CF will happen in the second quarter of next year, which means that we will be enrolling patients in the second half of next year,” Suliman said.
Lockhart said ReCode has shown the recovery of function in the gold-standard human cell model for both PCD and CF.
“In the PCD program, we’ve selected the lead mRNA We selected the lead delivery LNP and we’ve done full dose finding studies with safety and tox readouts. We’ve shown repeat administration in smaller animals and then we’ve done full dose finding in rats and non-human primates,” Lockhart said.
In the CF program, he added, ReCode has optimized the mRNA and drug formulation, and carried out repeated administration studies in mice. That program will also be moving into non-human primates later this year.
ReCode is also focused on developing therapies that deliver genetic cargo by applying gene editing/correction in target cells, including stem cells. The company plans to advance that modality through a collaboration that ReCode intends to launch with a “next-generation gene editing platform company” partner.
“Suffice to say, we have expansive interest from a wide variety of partners, not just on the technology synergy but on the SORT LNP platform itself,” Suliman said. “If you’re a biopharma partner and your interest is, for example, siRNA development, and you think about how to enhance the potency of your siRNA getting to the tissues and cell types of interest, the way to do that is with delivery.”
“We can actually enhance the potency of any genetic cargo by co-packaging that cargo with SORT LNP that will bring the two technologies together in a beautiful confluence of technology synergy,” she added.
Suliman joined ReCode in January when she succeeded Lockhart as CEO. Lockhart had been CEO of ReCode’s predecessor TranscripTx from 2014–2020, before he took the helm of ReCode when it was formed through an all-stock merger with TranscripTx. Lockhart oversaw the company’s successful oversubscribed $80 million Series A round, co-led by OrbiMed Advisors and Colt Ventures, with participation from MPM Capital, Vida Ventures, Hunt Technology Ventures, and Osage University Partners.
ReCode initially projected it would add $60 million to the Series B round when it began working to raise the additional capital.
All the original Series A investors were joined in the initial $80 million Series B round by co-leaders Pfizer Ventures and EcoR1 Capital, plus new investors that included Sanofi Ventures, as well as funds managed by Tekla Capital Management LLC, Superstring Capital and NS Investment.
As Suliman related on GEN’s Close to the Edge video series earlier this year, her career began as a physician in her native South Africa, where she received her MD from the University of Cape Town Medical School. She pivoted to investment banking about two decades ago, earning an MBA at Oxford University, then held positions at Lehman Brothers and later Petkevich & Partners.
A few years later, she embarked on a successful career as a biotech business development executive. At Gilead, Suliman held management roles of increasing responsibility between 2005 and 2010 and helped expand the company into new therapeutic areas, notably HIV, through M&A. She then held positions at Genentech and its parent company Roche, as well as at Theravance, where she put together a $1 billion profit-sharing partnership with Johnson & Johnson’s Janssen Biotech for its lead JAK inhibitor program before moving to Alector Therapeutics as president and COO.
“After I joined ReCode, we spent a few months together as a team really updating the strategy and execution plan for the company and for the SORT LNP platform,” Suliman recalled. “We hit the road on the financing in mid-April, and by mid-June, we will fully oversubscribed.”
The expanded Series B was co-led by new investors Leaps by Bayer and AyurMaya, with participation from Amgen Ventures. Alan Colowick, MD, MPH, managing director of Matrix, and Rakhshita Dhar, senior director of Venture investments Health at Leaps by Bayer, have joined ReCode’s Board of Directors.
“We have been incredibly fortunate in a challenging financing environment to connect with really sophisticated and thoughtful investors that understand the importance of following the science and generating good science and, importantly, understanding the importance of successful delivery as the key to unlocking the future of genetic medicine,” Suliman added.
“We really encourage others to stay the course and not give up, because if the science is compelling, the opportunity will be there.”
In this specific predicament, U.S. officials have to choose a strategy to deliver the aid without the perception of benefiting Hamas, a group the U.S. and Israel both classify as a terrorist organization.
When aiding people in war zones, you can’t just send money, a development strategy called “cash transfers” that has become increasingly popular due to its efficiency. Sending money can boost the supply of locally produced goods and services and help people on the ground pay for what they need most. But injecting cash into an economy so completely cut off from the world would only stoke inflation.
So the aid must consist of goods that have to be brought into Gaza, and services provided by people working as part of an aid mission. Humanitarian aid can include food and water; health, sanitation and hygiene supplies and services; and tents and other materials for shelter and settlement.
Due to the closure of the border with Israel, aid can arrive in Gaza only via the Rafah crossing on the Egyptian border.
The U.S. Agency for International Development, or USAID, will likely turn to its longtime partner on the ground, the United Nations Relief and Works Agency, or UNRWA, to serve as supply depots and distribute goods. That agency, originally founded in 1949 as a temporary measure until a two-state solution could be found, serves in effect as a parallel yet unelected government for Palestinian refugees.
USAID will likely want to tap into UNRWA’s network of 284 schools – many of which are now transformed into humanitarian shelters housing two-thirds of the estimated 1 million people displaced by Israeli airstrikes – and 22 hospitals to expedite distribution.
Since Biden took office, total yearly U.S. assistance for the Palestinian territories has totaled around $150 million, restored from just $8 million in 2020 under the Trump administration. During the Obama administration, however, the U.S. was providing more aid to the territories than it is now, with $1 billion disbursed in the 2013 fiscal year.
The United Nations Relief and Works Agency is a U.N. organization. It’s not run by Hamas, unlike, for instance, the Gaza Ministry of Health. However, Hamas has frequently undermined UNRWA’s efforts and diverted international aid for military purposes.
Humanitarian aid professionals regularly have to contend with these trade-offs when deciding to what extent they can work with governments and local authorities that commit violent acts. They need to do so in exchange for the access required to help civilians under their control.
Similarly, Biden has had to make concessions to Israel while brokering for the freedom to send humanitarian aid to Gaza. For example, he has assured Israel that if any of the aid is diverted by Hamas, the operation will cease.
This promise may have been politically necessary. But if Biden already believes Hamas to be uncaring about civilian welfare, he may not expect the group to refrain from taking what they can.
Security best practices
What can be done to protect the security of humanitarian aid operations that take place in the midst of dangerous conflicts?
Under International Humanitarian Law, local authorities have the primary responsibility for ensuring the delivery of aid – even when they aren’t carrying out that task. To increase the chances that the local authorities will not attack them, aid groups can give “humanitarian notification” and voluntarily alert the local government as to where they will be operating.
Under the current agreement between the U.S., Israel and Egypt, the convoy will raise the U.N. flag. International inspectors will make sure no weapons are on board the vehicles before crossing over from Arish, Egypt, to Rafah, a city located on the Gaza Strip’s border with Egypt.
The aid convoy will likely cross without militarized security. This puts it at some danger of diversion once inside Gaza. But whether the aid convoy is attacked, seized or left alone, the Biden administration will have demonstrated its willingness to attempt a humanitarian relief operation. In this sense, a relatively small first convoy bearing water, medical supplies and food, among other items, serves as a test balloon for a sustained operation to follow soon after.
In that case, the presence of U.S. armed forces might provoke attacks on Gaza-bound aid convoys by Hamas and Islamic jihad fighters that otherwise would not have occurred. Combined with the mobilization of two U.S. Navy carrier groups in the eastern Mediterranean Sea, I’d be concerned that such a move might also stoke regional anger. It would undermine the Biden administration’s attempts to cool the situation.
On U.N.-approved missions, aid delivery may be secured by third-party peacekeepers – meaning, in this case, personnel who are neither Israeli nor Palestinian – with the U.N. Security Council’s blessing. In this case, tragically, it’s unlikely that such a resolution could conceivably pass such a vote, much less quickly enough to make a difference.
Topher L. McDougal does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
“The majority of wound infections often manifest themselves immediately postoperatively, so close followup should take place […]”
Credit: 2023 Barbarewicz et al.
“The majority of wound infections often manifest themselves immediately postoperatively, so close followup should take place […]”
BUFFALO, NY- October 20, 2023 – A new research perspective was published in Oncoscience (Volume 10) on October 4, 2023, entitled, “Diagnosis and management of postoperative wound infections in the head and neck region.”
In everyday clinical practice at a department for oral and maxillofacial surgery, a large number of surgical procedures in the head and neck region take place under both outpatient and inpatient conditions. The basis of every surgical intervention is the patient’s consent to the respective procedure. Particular attention is drawn to the general and operation-specific risks.
Particularly in the case of soft tissue procedures in the facial region, bleeding, secondary bleeding, scarring and infection of the surgical area are among the most common complications/risks, depending on the respective procedure. In their new perspective, researchers Filip Barbarewicz, Kai-Olaf Henkel and Florian Dudde from Army Hospital Hamburg in Germany discuss the diagnosis and management of postoperative infections in the head and neck region.
“In order to minimize the wound infections/surgical site infections, aseptic operating conditions with maximum sterility are required.”
Furthermore, depending on the extent of the surgical procedure and the patient‘s previous illnesses, peri- and/or postoperative antibiotics should be considered in order to avoid postoperative surgical site infection. Abscesses, cellulitis, phlegmone and (depending on the location of the procedure) empyema are among the most common postoperative infections in the respective surgical area. The main pathogens of these infections are staphylococci, although mixed (germ) patterns are also possible.
“Risk factors for the development of a postoperative surgical site infection include, in particular, increased age, smoking, multiple comorbidities and/or systemic diseases (e.g., diabetes mellitus type II) as well as congenital and/ or acquired immune deficiency [10, 11].”
Continue reading the paper: DOI:https://doi.org/10.18632/oncoscience.589
Correspondence to: Florian Dudde
Keywords: surgical site infection, head and neck surgery
Oncoscience is a peer-reviewed, open-access, traditional journal covering the rapidly growing field of cancer research, especially emergent topics not currently covered by other journals. This journal has a special mission: Freeing oncology from publication cost. It is free for the readers and the authors.
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G77 Nations, China, Push Back On U.S. "Loss And Damage" Climate Fund In Days Leading Up To UN Summit
As was the case in primary school with bringing in presents, make sure you bring enough for the rest of the class, otherwise people get ornery...
This age old rule looks like it could be rearing its head in the days leading up to the UN COP 28 climate summit, set to take place in the United Arab Emirates in about six weeks.
At the prior UN COP 27, which took place in Egypt last year, the U.S. pushed an idea for a new World Bank "loss and damage" climate slush fund to help poor countries with climate change. But the G77 nations plus China, including many developing countries, are pushing back on the idea, according to a new report from the Financial Times.
The goal was to arrange how the fund would operate and where the money would come from for the "particularly vulnerable" nations who would have access to it prior to the upcoming summit in UAE.
But as FT notes, Pedro Luis Pedroso Cuesta, the Cuban chair of the G77 plus China group, has said that talks about these details were instead "deadlocked" over issues of - you guessed it - where the money is going and the governance of the fund.
The U.S.'s proposal for the fund to be governed by the World Bank has been rejected by the G77 after "extensive" discussions, the report says. Cuesta has said that the nations seek to have the fund managed elsewhere, but that the U.S. wasn't open to such arrangements.
Cuesta said: “We have been confronted with an elephant in the room, and that elephant is the US. We have been faced with a very closed position that it is [the World Bank] or nothing.”
Christina Chan, a senior adviser to US climate envoy John Kerry, responded: “We have been working diligently at every turn to address concerns, problem-solve, and find landing zones.” She said the U.S. has been "clear and consistent" in their messaging on the need for the fund.
Cuesta contends that the World Bank, known for lending to less affluent nations, lacks a "climate culture" and often delays decision-making, hindering quick responses to climate emergencies like Pakistan's recent severe flooding.
The G77 coalition voiced concerns about the World Bank's legal framework potentially limiting the fund's ability to accept diverse funding sources like philanthropic donations or to access capital markets.
With just days left before the UN COP 28 summit, the World Bank insists that combating climate change is integral to its mission and vows to collaborate on structuring the fund.