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- Funding will advance development of Rejuvenate’s one-time gene therapy RJB-0402 for the treatment of desmoplakin gene variant arrhythmogenic cardiomyopathy SAN DIEGO--(BUSINESS WIRE)-- Rejuvenate Bio, announced today that the California Institute for Regenerative Medicine (CIRM) has awarded the company a $4M grant to complete IND-enabling activities for the development of RJB-0402 for the treatment of desmoplakin gene variant arrhythmogenic cardiomyopathy (DSP ACM). RJB-0402 is a novel systemically administered investigational AAV8 gene therapy that drives liver specific expression of FGF21 protein, targeting multiple key pathological drivers of DSP ACM. Since the DSP gene is too large for gene replacement therapy, novel strategies are needed to treat DSP ACM. FGF21 has known salutary effects on cardiac dysfunction as well as ventricular arrhythmias, adipogenesis, inflammation, and fibrosis, all of which are DSP ACM hallmarks. Furthermore, clinical efficacy of RJB-0402 in DSP ACM may form the basis for the treatment in other forms of ACM. “DSP ACM is a rare, severe, life-threatening, and debilitating disease that typically manifests in young adults as a high risk of life-threatening ventricular arrhythmias, sudden cardiac death, and progression to heart failure,” said Dan Oliver, CEO & Co-Founder, Rejuvenate Bio. “There is currently no disease modifying therapy for patients with this disease, and our gene therapy RJB-0402 addresses a significant unmet medical need.” “The funding and strategic support from CIRM will accelerate development of our gene therapy candidate RJB-0402 into clinical trials for DSP ACM patients in desperate need of new therapies,” said Noah Davidsohn, Ph.D., Chief Scientific Officer & Co-Founder, Rejuvenate Bio. “We are confident that RJB-0402, a one-time gene therapy, could be a transformative regenerative medicine and the first disease modifying therapy to address the unmet medical need of DSP ACM patients, and the recent funding from CIRM will enable us to initiate our first in human clinical trial.” Nonclinical proof-of-concept studies in the ACM mouse model showed that RJB-0402 significantly improved cardiac structure, function, and markedly reduced the arrhythmia burden, normalizing premature ventricular contractions (PVCs) to wild type levels. The clinical relevance of these efficacy signals provides a scientific rationale for further development as a therapeutic with the potential to meaningfully impact patients’ survival, symptoms, and quality of life. “Our goal is to move the most promising research forward,” said Dr. Abla Creasey, Vice President of Therapeutics Development at the California Institute for Regenerative Medicine (CIRM). “A one-time gene therapy treatment for patients with this rare cardiac disease DSP ACM, would have significant impact for patients with this degenerative disorder. We look forward to supporting Rejuvenate Bio in bringing this regenerative therapy to patients with this degenerative disease.” About Desmoplakin Arrhythmogenic Cardiomyopathy (DSP ACM) DSP ACM is a severe, life-threatening, and debilitating, rare autosomal recessive disease that results in ventricular arrhythmias that are often life threatening and progressive cardiac dysfunction caused by fibrofatty replacement of ventricular myocardium which can lead to heart failure for which no disease modifying therapies exist. While more than 10 different genes have been implicated in this heterogeneous disease, the majority involve one or more variants in desmosomal genes which are key components of the cardiac intercalated disc that are essential for the electrical and mechanical coupling of cardiomyocytes. These multiprotein complexes work together to provide cardiac mechanical integrity and strength as well as electrical communication and synchronization. While the exact prevalence of DSP ACM is unknown, it is estimated to affect an estimated 30,000-50,000 people in the United States. About Rejuvenate Bio Rejuvenate Bio is a biotechnology company dedicated to developing novel gene therapies for chronic age-related diseases. Rejuvenate Bio has built a gene therapy pipeline with huge potential in chronic disease by utilizing clinically validated gene targets and a delivery approach that ensures well tolerated, durable expression. Founded on scientific research developed at the Wyss Institute at Harvard Medical School, Rejuvenate Bio has developed groundbreaking therapies to treat chronic age-related disease in both humans and animals. The company is headquartered in San Diego, CA. For more information, visit . About California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today’s most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is the world’s largest institution dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go to .

SAN DIEGO--(BUSINESS WIRE)-- Rejuvenate Bio, today announced new preclinical efficacy data for RJB-0402, a gene therapy targeting key disease-mediating pathways. RJB-0402 demonstrated efficacy in a mouse model of arrhythmogenic cardiomyopathy (ACM), an inherited disease caused by mutations in one of several genes encoding desmosomal proteins. A single dose of RJB-0402 was able to significantly improve cardiac function, preserve cardiac structure, and dramatically reduce premature ventricular contractions (PVCs) to normal levels. RJB-0402 was superior to gene replacement regarding its ability to normalize arrhythmias and demonstrated comparable effect on preservation of cardiac structure and function in this mouse model of ACM, which recapitulates human disease by disrupting the structure of the cardiac desmosome. Desmosomal proteins are essential for maintaining the integrity of cardiac muscle and individual muscle cells. Desmosomal protein mutations can disrupt the normal function of the heart and may result in life threatening heart rhythms and other cardiac issues, such as ACM, a rare and severe genetic heart condition that can be debilitating and life threatening. The current standard of care for patients with ACM consists of medications targeting arrhythmia management and heart failure, implantable cardioverter defibrillators (ICDs), and cardiac catheter ablations, none of which are curative. Even with optimal treatment, life-threatening arrhythmias and disease progression still occur, and can lead to heart failure. There are no disease-modifying treatments for ACM, other than cardiac transplant for late-stage disease. ACM therefore presents a profound unmet medical need for patients with the disease. “RJB-0402 shows exciting potential to be a significant breakthrough for patients suffering from this severe, life-limiting disease, who have an urgent need for better treatment options. If this approach proves effective to treat ACM, it would have a dramatic impact on the profound burden this disease has on patients and their families,” said Hugh Calkins, MD, Professor of Cardiology and Director of the Johns Hopkins Arrhythmia Service and the ARVD/C Program. “What makes RJB-0402 especially promising is its superior performance in the ACM nonclinical model, outperforming gene replacement therapies in reducing PVCs. Since RJB-0402 is not a mutation-specific gene therapy, this suggests that it has the potential to address all causes of ACM including those without known mutations, estimated to be 130,000 individuals, rather than being limited to a specific genetic subgroup, like gene replacement therapies,” said Daniel Oliver, CEO & Co-Founder, Rejuvenate Bio. “ARVC is a progressive genetic disorder that can affect multiple generations of family members. One of the first symptoms of ARVC can be sudden cardiac arrest, which can lead to sudden death. Therapies that are agnostic of the individual’s specific mutation are a vital avenue of investigation and we are thrilled to learn of Rejuvenate Bio’s continued progress in this area. This research gives much-needed hope to all families affected by ARVC,” said Alice Lara, President of the Sudden Arrhythmia Death Syndromes (SADS) Foundation. RJB-0402 is a liver-targeting adeno-associated virus vector-based gene therapy that drives over expression of FGF21. Since the doses required to overexpress FGF21 in the liver are meaningfully lower than those required for traditional AAV gene replacement therapies, this approach may have a beneficial effect on the safety pro the investigational product and could also dramatically reduce manufacturing costs. The initial clinical study for RJB-0402 will focus on patients with Desmoplakin-related arrhythmogenic cardiomyopathy (DSP ACM) at high risk of life-threatening ventricular arrhythmias and sudden cardiac death. “We see great promise for this therapy to treat this severe, life-threatening disease and improve the quality of life for patients with DSP ACM and look forward to engaging with the FDA in the near future to align on the requirements to initiate an IND,” said Deborah Ascheim, MD, Chief Medical Officer, Rejuvenate Bio. About Rejuvenate Bio Rejuvenate Bio is a gene therapy company focused on treating chronic disease based upon breakthrough technology developed at the Wyss Institute at Harvard University. Rejuvenate Bio utilizes gene therapy, proprietary targets, and tools to bring treatments to patients suffering from chronic conditions. The company is developing a pipeline of therapies with applications in cardiac and metabolic diseases. The company raised a Series A financing in 2021 led by Kendall Capital Partners, Digitalis Ventures, KdT Ventures and V Capital. Rejuvenate Bio is based in San Diego for more information, visit .

Researchers have identified a new mutation that leads to the cardiac disease arrhythmogenic cardiomyopathy (ACM). They assessed the effect of this mutation on heart muscle cells and obtained new insights into the underlying mechanism that causes the disease. The results of this study could contribute to the development of new treatments for ACM. Researchers from the group of Eva van Rooij in collaboration with the UMC Utrecht identified a new mutation that leads to the cardiac disease arrhythmogenic cardiomyopathy (ACM). They assessed the effect of this mutation on heart muscle cells and obtained new insights into the underlying mechanism that causes the disease. The results of this study, published on March 2nd in Stem Cell Reports, could contribute to the development of new treatments for ACM. Desmosomes Millions of heart muscle cells contract to let the heart fulfill its pumping function. To make sure these contractions are executed well, it is important that the individual heart muscle cells communicate with each other. Therefore, heart muscle cells have to be tightly connected with each other. In a healthy heart, these connections are made up of complex protein structures that form a bridge between the cells, so called desmosomes. When mutations occur in genes that contribute to these structures, this can lead to the development of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive and often hereditary disease in which the heart fails to contract properly. Even though 1 in 5000 people develop ACM throughout life, a lot remains unknown about the disease and no effective treatment options exist to cure patients. Discovery of a new mutation "We investigated the genetic material of an ACM patient and encountered a previously unknown mutation in the gene desmoplakin," says first author of the study Sebastiaan van Kampen. Desmoplakin is one of the genes that is responsible for the formation of desmosomes. To investigate the role of this mutation in ACM onset, the researchers cultured heart muscle cells from the patient in the lab. Van Kampen: "We compared these heart muscle cells to the same heart muscle cells in which we repaired the mutation using CRISPR/Cas9. The heart muscle cells that contained the mutation turned out to be less tightly connected." In addition, the researchers discovered that these cells have fewer of ion channels. These channels are crucial for efficient propagation of the action potential, an electrical signal that stimulates contraction, between heart muscle cells. From this, they concluded that the new mutation can lead to ACM in patients. Underlying mechanism Multiple mutations are known to lead to ACM. Nevertheless, the underlying mechanism that leads to the disease remains largely unknown. To change this, the researchers used the cultured heart muscle cells from the patient as a model for the disease. They discovered that a protein named PITX2 is more highly expressed in the "diseased" heart muscle cells and that this protein is in part responsible for the loss of desmosomes and ion channels. "When we removed the protein from the diseased heart muscle cells, the levels of ion channels and desmosomal proteins in the cells of the patient showed a remarkable recovery," explains Van Kampen. The PITX2 protein thus plays an important role in the changes in the mutated heart muscle cells. Future treatments The study, published in Stem Cell Reports, can potentially contribute to the development of new treatments for ACM. Furthermore, the findings from this study offer new insights into the development of ACM that can be valuable for future research. "Although we don't know how the new mutation leads to increased levels of PITX2, we see the same happening in a second mutation. It's possible that increased levels of PITX2 lead to ACM in the context of many more mutations," says Eva van Rooij, group leader at the Hubrecht Institute and last author of the study. More research into these different mutations is therefore essential.