The Salk Institute for Biological Studies

Data demonstrate engineered tRNA from company's first development candidate restores protein production to clinically meaningful levels in two disease models driven by the same premature termination codon CAMBRIDGE, Mass., Dec. 9, 2024 /PRNewswire/ -- Alltrna, a Flagship Pioneering company unlocking transfer RNA (tRNA) biology and pioneering tRNA therapeutics to regulate the protein universe and resolve disease, today announced the presentation of new preclinical data, including of the company's first tRNA development candidate, AP003. AP003 is a chemically modified, engineered tRNA oligonucleotide in a clinically validated, liver-directed lipid nanoparticle (LNP) that can readthrough the arginine to TGA (Arg-TGA) premature termination codon (PTC). A single dose of AP003 tRNA showed robust in vivo restoration of protein production to clinically meaningful levels in two transgenic Stop Codon Disease mouse models, methylmalonic acidemia (MMA) and phenylketonuria (PKU). The data were presented at the Nature Conference: RNA at the Bench and Bedside IV, taking place December 9-11 at The Salk Institute in La Jolla, California. "These data represent an important milestone for Alltrna, demonstrating robust in vivo activity and clinically relevant protein restoration across two disease models representing two different inborn errors of metabolism driven by the same premature termination codon," said Michelle C. Werner, CEO of Alltrna and CEO-Partner at Flagship Pioneering. "We believe these data support the potential for a basket approach to developing AP003 for the treatment of many rare genetic liver diseases caused by an Arg-TGA PTC, including the organic acidemias and aminoacidopathies represented by our MMA and PKU Stop Codon Disease mouse models. We look forward to advancing our IND-enabling studies for AP003." In an MMA Stop Codon Disease mouse model, developed by Alltrna and collaborators, a single dose of the tRNA component of AP003 (tRNA-3) in a LNP delivery system restored in vivo protein levels of methylmalonyl-CoA mutase (MMUT) to approximately 25% of wildtype levels at Day 4, well above the 1-2% protein rescue considered to be clinically meaningful in MMA by key opinion leaders. Protein levels remained above 1-2% of wildtype 14 days after dosing, which was the longest time point tested. In a new Stop Codon Disease mouse model of PKU, developed by Alltrna, a single dose of AP003 demonstrated phenylalanine hydroxylase (PAH) restoration to 7% of wildtype levels within 72 hours, exceeding the clinically relevant 3% protein rescue target defined by key opinion leaders. Further, this PAH protein restoration resulted in a meaningful 76% reduction of phenylalanine (Phe) levels from baseline, as PAH is the enzyme responsible for breaking down Phe. When PAH is mutated or deficient, Phe accumulates to toxic levels, causing the hallmark elevated Phe levels observed in PKU. "Based on tRNA's critical role in protein translation, a single tRNA medicine is uniquely positioned to address multiple diseases that have a shared mutation. We are excited to see that our engineered tRNA can in fact achieve significant restoration of protein production above clinically relevant target levels in both MMA and PKU, where a premature termination codon would otherwise create a truncated or missing protein," said Chris Henderson, Ph.D., Chief Scientific Officer of Alltrna. "In addition, to our knowledge, these are the first preclinical data with a tRNA candidate demonstrating that protein restoration leads to meaningful changes in levels of a clinical biomarker (Phe) that is recognized as a registrational endpoint in humans." Dr. Henderson continued, "We are delighted to have generated such promising in vivo data in two models of Stop Codon Disease. The fact that a single engineered tRNA acting on the same premature termination codon can show readthrough and protein restoration in two distinct genetic contexts provides support for Alltrna's vision of treating patients carrying the same PTC across different diseases in a given tissue. As a first example, we look forward to developing AP003 through a basket approach as a novel treatment for inborn errors of metabolism affecting the liver." About AP003 AP003 is a chemically modified, engineered tRNA oligonucleotide encapsulated in a clinically validated, liver-directed lipid nanoparticle that is in development for the treatment of patients with liver Stop Codon Disease that carry an arginine to TGA (Arg-TGA) nonsense mutation in the affected gene. The Arg-TGA mutation occurs when a single base of the arginine-encoding codons, CGA and AGA, mutates to UGA (TGA in DNA), a termination codon for which there is no corresponding amino acid. AP003 is designed to readthrough the premature termination codon to reintroduce arginine into the growing polypeptide chain at the time of RNA-to-protein translation and restore protein production. Arg-TGA is the most frequent nonsense mutation (21-22%) occurring in human genetic diseases. About Stop Codon Disease Stop Codon Disease encompasses thousands of rare and common diseases that stem from premature termination codons (PTC) also called nonsense mutations, where the code for an amino acid has been mutated into a premature "stop" codon. This results in a truncated or shortened protein product with no or altered biological activity that causes disease. Approximately 10% of all people with a genetic disease have Stop Codon Disease, representing approximately 30 million people worldwide. Alltrna is engineering tRNA medicines that can read these PTC mutations and deliver the desired amino acid, thereby restoring the production of the full-length protein. About Alltrna Alltrna unlocks tRNA biology to treat disease. The company's platform incorporates AI/ML tools to develop and deliver diverse programmable molecules with broad therapeutic potential. Alltrna has an unprecedented opportunity to advance a single tRNA medicine to readthrough premature stop codons and unify treatment across a wide range of diseases with the same underlying genetic mutations. Alltrna was founded in 2018 by Flagship Pioneering. For more info, visit . Media Contacts Jessica Yingling, Ph.D., Little Dog Communications Inc., [email protected], +1.858.344.8091 Josephine Zorbo, Ph.D., Flagship Pioneering, [email protected] SOURCE Alltrna WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Researchers at UC San Diego plan to develop a wireless, multi-modal electrode system wired to the brain to restore vision after an eye transplant. Bringing together more than 40 scientists, doctors and industry experts, the team hopes to make vision-restoring whole-eye transplants a reality. Their system could wire the optic nerve to the brain with high-end precision. Professor Shadi Dayeh, in the Department of Electrical and Computer Engineering, leads the UCSD team on that front. Scripps Research Associate Professor in the Department of Molecular Medicine, Anne Hanneken, will lead a team set to advance neuroprotective surgical protocols, perfusion techniques and monitoring systems. They aim to support the long-term viability of the whole eyes and the surgical transplant procedure. Hanneken and Dayeh will work jointly with Dr. Jeffrey Goldberg, chair of ophthalmology at the Byers Eye Institute at Stanford University. They join principal investigator, Dr. José-Alain Sahel, professor and chair of the Department of Ophthalmology at the University of Pittsburgh. Sahel co-directs the initiative. Dayeh says the electrode interface technology and end-to-end systems developed at UCSD will map the human eye, optic nerve and visual cortex at high resolutions. It could also help regenerate the optic nerve after an eye transplant. According to an article on the UCSD website, the biggest challenge faced by the team comes in the form of moving whole eye transplants from aesthetic to functional. The researchers need to figure out how to regenerate the optic nerve, which connects the eye to the brain. Dayeh’s group invented a biocompatible electrode interface that uses platinum nanorods (PtNRs) that can be applied in various areas of the central and peripheral nervous system (CNS and PNS, respectively). These devices come in multiple forms, such as electrode arrays with thousands of channels to capture brain activity in high resolution. In the early process of their project, the team aimed to use a grid composed of tens of thousands of light-emitting diodes. These stimulate the retina and map topographical organization of the retinal-optic nerve-brain pathways in animals in humans. In later phases, the group plans to use human-grade, inflatable electrodes developed to stimulate and regenerate the optic nerve. “The scientific questions we are addressing now are so complicated and complex that you really need the best and brightest collaborators with multidisciplinary expertise to make a true impact,” Hanneken said. “Our recent success in restoring light signaling in postmortem human organ donor eyes was only possible with a great team. This team approach will now allow us to reconsider the prediction made by Dr. Roger Guillemin, Nobel Laureate in Physiology and former president of the Salk Institute, who told me 30 years ago that we would be performing whole eye transplants in my lifetime.”

SAN DIEGO--( BUSINESS WIRE )-- Curebound launched its new Curebound Cancer Challenge today. An evolution of Curebound’s renowned Padres Pedal the Cause event, Curebound Cancer Challenge represents a new and elevated fundraising challenge experience. It aims to increase community participation and accelerate Curebound toward its goal of investing $100 million in cancer research through collaborative grants, public/private partnerships and targeted investments that are anchored in San Diego, with the potential to spread nationally through scientific collaborations. Over the past 10 years, Curebound’s signature community event, Padres Pedal the Cause, has brought together 20,000+ people during one of the largest cancer research fundraising events on the West Coast to raise $24.5 million. Building on this strong foundation, Curebound is raising the stakes on its fundraising goals, moving the event to UC San Diego, and inviting more people to ride, run, walk, spin, volunteer and donate on August 2, 2025, to advance cancer research. Register for Curebound Cancer Challenge HERE . Situated in La Jolla among numerous world-renowned research organizations and Curebound research partner institutions — Moores Cancer Center at UC San Diego, Salk Institute, Sanford Burnham Prebys, Rady Children’s Hospital, La Jolla Institute for Immunology, and Scripps Research — the UC San Diego site for Curebound Cancer Challenge will put a spotlight on the San Diego scientific community that has made tremendous strides in the race to find cures for cancer as Curebound presents an enhanced fundraising event experience. Curebound Cancer Challenge will feature three world-class rides along San Diego’s Torrey Pines coastline, a family friendly 5K, a new 10K run, 50-minute spin classes, entertainment, family activities and a team village where Curebound Cancer Challenge teams can gather, honor loved ones battling cancer, and celebrate their fundraising to put an end to cancer. A generous donor has kicked off fundraising for the event with a $1.1 million lead gift. Pedal the Cause San Diego was founded by Bill Koman, CEO, Koman Group, Curebound Chairman , a two-time lymphoma survivor, and his wife Amy. Grateful for the life-saving care Bill received, the Koman family is committed to ensuring the same outcome for others. In 2013, Pedal the Cause began at UC San Diego with a few hundred riders committed to supporting cancer patients and their families. In a partnership with the San Diego Padres, the event moved to Petco Park in 2016 and became known as Padres Pedal the Cause. The San Diego Padres have been dedicated Curebound partners, providing unwavering support. Since then, the event has grown significantly, raising $24.5 million. Executive Vice President at the San Diego Padres Tom Seidler says, “The Padres have been honored to partner with Pedal the Cause and host this incredible community at Petco Park through seven years of tremendous growth, community building, and impact. We look forward to supporting the Curebound Cancer Challenge as it advances the organization’s mission to raise funds and invest in innovative cancer research.” “We are excited to welcome the Curebound Cancer Challenge to its new home at UC San Diego,” said John M. Carethers, MD, Vice Chancellor of Health Sciences at UC San Diego. “Curebound funds important cancer research that is relevant to our institution — including our NCI-designated Moores Cancer Center — as well as other institutions on the Torrey Pines Mesa, and we look forward to being an integral part of its continued growth and success towards prevention and finding treatments for cancer.” Curebound Cancer Challenge is attracting corporate support as well. Sponsors include Edward Jones San Diego , UC San Diego , Janux Therapeutics , Vividion Therapeutics , JP Morgan , Lusardi Construction , Jet AMG , Pfizer , Corza Health , WE Oneil Construction , and Bernstein Private Wealth Management . Victor Manzanilla, Edward Jones Financial Advisor and Cancer Challenge Team Captain, says, “Cancer touches so many families, we are thrilled to be part of raising funds needed to accelerate studies that will get us closer to a cure. We’re looking forward to riding as Team Edward Jones in August.” For more information about supporting Curebound Cancer Challenge, email Liz DeGeronimo at liz@curebound.org . Register for Curebound Cancer Challenge at https://www.curebound.org/curebound-cancer-challenge . About Curebound Curebound is a philanthropic organization that invests in cancer research with the power to save lives. Through collaborative grants, corporate partnerships, and strategic investments, Curebound’s aim is to significantly accelerate better prevention, detection, and treatments for cancer. Headquartered in the major U.S. biotech hub of San Diego, amid 3,000+ life sciences companies, leading health systems, and world-class research institutions, Curebound partners with these organizations to forge interdisciplinary collaboration, foster knowledge sharing, and fund pioneering cancer research. So far, Curebound has funded $37+ million in cancer research, awarding 123 study grants for 17 types of pediatric and adult cancers with one vision: cures in our lifetime. Join us - www.curebound.org .