NODAL

Bricklayer, banker, teacher -- choosing a career is one of the most exciting and important decisions in our lives. At the beginning of embryonic development, our cells are also faced with this decision. Some of them become blood cells, others muscle cells and still others become nerve cells. A team has now unveiled how the antagonism between the two signaling molecules FGF and BMP influences the stem cells' career choice. Particularly interesting is the fact that stem cells can also direct their own fate. These findings help to better understand cell differentiation and could thus be a basis for future developments in the field of targeted culturing of tissue in cell replacement therapies. Bricklayer, banker, teacher -- choosing a career is one of the most exciting and important decisions in our lives. At the beginning of embryonic development, our cells are also faced with this decision. Some of them become blood cells, others muscle cells and still others become nerve cells. A team led by Christian Schröter at the Max Planck Institute of Molecular Physiology in Dortmund has now unveiled how the antagonism between the two signaling molecules FGF and BMP influences the stem cells' career choice. Particularly interesting is the fact that stem cells can also direct their own fate. These findings help to better understand cell differentiation and could thus be a basis for future developments in the field of targeted culturing of tissue in cell replacement therapies. People usually make their career choice in their teens. In the growing embryo, however, stem cells make this decision just a few days after the fusion of egg and sperm. At this point gastrulation begins and the so-called germ layers form. After gastrulation, the embryo can be thought of as an onion with three layers: the ectoderm, the mesoderm and the endoderm. These will later become the internal organs. Cocktail of signal molecules A cocktail of different signaling molecules such as BMP, FGF, Wnt and Nodal plays a decisive role in determining what a stem cell in the early embryo will eventually become. This cocktail is mixed by the surrounding extraembryonic tissue and -- depending on its mixture -- e.g. heart or nerve cells are formed. The composition of the various signal cocktails is well understood. However, the role of one ingredient, fibroblast growth factor (FGF), which plays an important role in stem cell migration and growth, still remains unclear to a large extent. For the first time scientists led by Christian Schröter could show that FGF acts as an antagonist of the signal molecule BMP. If there is little FGF, BMP has a strong effect and heart cells and extraembryonic mesoderm are more likely to develop. However, if there is much FGF, the effect of BMP is suppressed and cells of the posterior body axis are more likely to grow. Instructive or intuitive? In the past, parents played a decisive role in determining their children's career choices. In the development of stem cells, a similarly instructive process -- based on the secretion of signaling molecules -- was assumed by developmental biologists. However, the researchers' results indicate that stem cells are not exclusively guided by external signals, but can indeed take their fate into their own hands. Even if, for example, stem cells in the culture dish were instructed by continuous FGF addition to form heart cells, groups of completely different cell types developed nevertheless. The scientists suspect that this supposedly intuitive process is a based on a community effect: Cells that are close together manage to communicate with each other. They send out signals themselves so that the neighboring cells develop in the same direction: They once become the same cell type and take up the same profession. "Our research contributes to a better understanding of the process itself and the key players involved in cell differentiation," explains Christian Schröter. "In the future, these and other findings could help to generate specific cell types from stem cells in a targeted manner, for example to replace dead tissue after a heart attack. So far, selective culturing of specific cell types is not yet possible."

“In an era where a lot of financings are down rounds or very diluted, this was a very attractive option for us," Recludix's CEO Nancy Whiting said of the Sanofi deal. Sanofi is paying Recludix Pharma $125 million and offering up more than $1.2 billion in biobucks for a pact taking aim at multiple immunological and inflammatory indications. “It's a great deal for Recludix; we're really thrilled,” Nancy Whiting—who joined as the biotech’s first CEO in 2021 after more than 14 years at Seagen—told Fierce Biotech in an interview. “It's a really high-value deal and I think it'll be transformational for Recludix.”   The agreement centers around Recludix’s preclinical STAT6 inhibitor. The first-in-class oral small-molecule drug works on the SH2 domain, which was historically considered an undruggable target. Now, Recludix thinks it has cracked the code by blocking STAT6, a key nodal transcription factor that selectively mediates downstream IL-4 and IL-13 signaling, which drives type 2 inflammatory diseases like asthma, atopic dermatitis and allergies. Sanofi has signed on to help develop and potentially commercialize the California biotech’s program, with expectations of entering the clinic in 2025. "Recludix’s approach to targeting STAT6 has significant potential for a number of I&I diseases, especially where a precisely tailored oral therapy could best fit within the patient’s needs at various stages of disease," Frank Nestle, M.D., Sanofi’s chief scientific officer and global head of research, said in a July 20 release.   Under the terms of the deal, Recludix will advance STAT6 inhibitors from preclinical research until the start of phase 2 trials, when Sanofi will take over clinical development. The French Big Pharma will also be responsible for commercialization activities and have global rights for any small-molecule STAT6 inhibitors that make it to market. In addition to the near-term $125 million payment, Sanofi could potentially dole out more than $1.2 billion for development, regulatory and sales milestones alongside royalties on possible future sales. Sanofi is also giving Recludix the option to participate in U.S. profit or loss share. “An option for Recludix to participate in a 50/50 U.S. profit share is really huge,” Whiting said, citing the ability for the biotech to participate in the development and economics of the drug in a meaningful way. “This deal really helps validate that the work that we've done and the steps forward in the science we've made are really significant,” the CEO added. “In an era where a lot of financings are down rounds or very diluted, this was a very attractive option for us to bring in some non-dilutive capital, help continue to push this program forward and make sure it has absolutely everything it needs to be successful.”

Sanofi signed a strategic collaboration with Recludix Pharma to develop oral small-molecule STAT6 inhibitors for patients with immunological and inflammatory diseases, the latter company said Thursday. The deal represents the second early-stage agreement for Sanofi this week, having unveiled a partnership on Monday with Scribe Therapeutics.Under the latest collaboration, Sanofi will have global rights to small-molecule STAT6 inhibitors, with Recludix advancing them from preclinical research and development through to the start of Phase II studies. The French drugmaker will subsequently assume development and commercialisation responsibilities, with Recludix having an option to participate in US profit/loss share.Recludix noted that inhibiting STAT6 - a key nodal transcription factor that selectively mediates downstream signalling of IL-4 and IL-13 – offers the potential to treat patients with multiple Type 2 inflammatory dermatological and respiratory diseases. "Recludix's approach to targeting STAT6 has significant potential…especially where a precisely tailored oral therapy could best fit within the patient's needs at various stages of disease," remarked Frank Nestle, Sanofi's global head of research.As part of the agreement, Sanofi will make near-term payments of $125 million, with Recludix eligible for more than $1.2 billion in potential milestones, as well as up to double-digit sales royalties.