PEDS1

On July 9th, 2024, the U.S. FDA approved Arcutis Biotherapeutics' ZORYVE® (roflumilast) for treating atopic dermatitis (AD), the most common type of eczema affecting millions in the U.S. This once-daily, steroid-free cream could become a new standard of care for AD. The approval underscores the growing importance of researching Phosphodiesterase 4 (PDE4) and other PDEs as immunomodulatory targets for various inflammatory diseases. Sino Biological, and its subsidiary SignalChem Biotech, support drug discovery and development targeting PDEs by providing a broad range of PDE families and isoforms. Mechanism of Action Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor that reduces inflammation by increasing cyclic adenosine monophosphate (cAMP) levels, an important molecule in regulating inflammation. PDE4, which breaks down cAMP, has four subtypes (PDE4A, PDE4B, PDE4C, PDE4D) and about 20 isoforms. The anti-inflammatory effects of PDE4 inhibitors are mainly due to inhibiting PDE4B and PDE4D, which are highly expressed in immune cells. By inhibiting these subtypes, roflumilast raises cAMP levels, decreasing pro-inflammatory mediators (e.g., TNF alpha, IL-4, IL-5, IL-13, IL-17A, IL-17F, IL-22) and increasing the anti-inflammatory mediator IL-10. This helps manage inflammatory conditions like atopic dermatitis, alleviating symptoms such as redness, itching, and swelling. PDE4 inhibitors mechanism of action. DOI:10.1517/13543784.2015.1094054 Phosphodiesterases (PDEs) as drug targets PDE enzymes control essential body functions by managing cAMP and cGMP levels. Various PDE inhibitors are developed for diseases: PDE1/2 for cardiovascular and neurological disorders; PDE4 for COPD and atopic dermatitis; PDE5 for erectile dysfunction and pulmonary arterial hypertension; PDE6 for retinal diseases; and PDE7 for inflammatory and autoimmune problems. In summary, PDE inhibitors are powerful tools and hold great promise as drug targets for wide-ranging therapeutic applications. Sino Biological’s Offering to Support Phosphodiesterases (PDEs) Research Sino Biological, along with its subsidiary SignalChem Biotech, is at the forefront of advancing drug development, offering a wide variety of recombinant PDE families and isoforms, to facilitate research on PDEs. Partner with us and visit our website to learn more about how we can best work together to accelerate the PDEs research.

Early non-human primate (NHP) data for P-KLKB1-101 demonstrate successful liver gene editing approaching human therapeutic range with a favorable safety and tolerability profile Preclinical P-FVIII-101 data highlight sustained Hemophilia A correction following a single dose and support potential for repeat dosing and precise tuning of Factor VIII levels Promising early data further validate Company's fully non-viral delivery platform and transposon technologies SAN DIEGO, May 9, 2024 /PRNewswire/ -- Poseida Therapeutics, Inc. (Nasdaq: PSTX), a clinical-stage allogeneic cell therapy and genetic medicines company advancing differentiated non-viral treatments for patients with cancer and rare diseases, today highlights new preclinical data supporting the potential of its fully non-viral lead genetic medicines programs and related platform technologies. The data was included in three oral and three poster presentations at the American Society of Gene and Cell Therapy (ASGCT) 2024 Annual Meeting, being held in Baltimore, MD and virtually on May 7-11, 2024. "Poseida's unique and proprietary toolkit, which enables non-viral gene insertion, high-fidelity gene editing, and associated delivery and manufacturing technologies, has been the driving force behind our emerging genetic medicines programs and our clinical stage allogeneic CAR-T pipeline," said Blair Madison, Ph.D., Chief Scientific Officer, Gene Therapy at Poseida Therapeutics. "Starting with our recent R&D Day, and continuing with ASGCT, we have showcased the maturity and power of our tools specific to enabling a fully non-viral and potentially tunable approach to in vivo genetic medicine. We believe this could provide our medicines with a superior profile featuring a minimized risk of off-target effects that can be customized to each patient, when appropriate. Taken together, these data give us confidence as we continue to validate our non-viral approach, seeking to achieve durable correction in patients suffering from rare diseases such as Hereditary Angioedema and Hemophilia A." Oral Presentations Title: Highly Specific Non-Viral Gene Editing with P-KLKB1-101 for Hereditary Angioedema Presenting Author: Blair Madison, Ph.D., Poseida Therapeutics, Inc. Session Title: Correction of Genetic Disorders of the Blood and Immune System Presentation Date/Time: Thursday, May 9, 2024, 1:30 - 1:45 PM ET Location: Room 314-317 Abstract Number: 170 Hereditary Angioedema (HAE) is a rare inherited disorder characterized by recurrent episodes of fluid accumulation outside of blood vessels, causing rapid swelling of tissues. HAE patients have significant unmet need for a durable, effective, and convenient treatment option that eliminates recurrent attacks. P-KLKB1-101 is a fully non-viral investigational gene editing therapy designed to enable high fidelity editing at pre-kallikrein, or KLKB1, for targeted correction of HAE. It utilizes the Cas-CLOVER™ nuclease to achieve clean site-specific gene editing that is engineered for high specificity. In pre-clinical studies, P-KLKB1-101 demonstrates excellent efficiency editing liver cells with off-target edits <0.1% over a wide range of lipid nanoparticle (LNP) concentrations. Poseida's gene editing delivery technologies, including novel ionizable lipid and LNP, enable a highly controlled dose response. Interim non-human primate (NHP) data demonstrate favorable tolerability and liver editing approaching the desired therapeutic range. Development of P-KLKB1-101 is ongoing, including continuation of dose-finding studies in NHPs, CMC manufacturing, scale-up, and additional preparations for IND-enabling studies. Title: Sustained FVIII Expression with a Tolerable, Titratable, Fully Non-Viral Gene Therapy for Hemophilia A Presenting Author: Brian Truong, Ph.D., Poseida Therapeutics, Inc. Session Title: Liver Genetic Diseases Presentation Date/Time: Thursday, May 9, 2024, 5:00 - 5:15 PM ET Location: Room 324-326 Abstract Number: 210 P-FVIII-101 is a fully non-viral gene insertion-based therapy for the treatment of Hemophilia A, an X-linked bleeding disorder caused by a deficiency in coagulation Factor VIII (FVIII). It utilizes Poseida's proprietary transposon technology combined with nanoparticle delivery to achieve site-specific gene insertion into DNA. Data demonstrate that a single dose of P-FVIII-101 achieves Hemophilia A disease correction with sustained FVIII expression observed over the 13-month duration of the mouse study. The pre-clinical data also support the potential for repeat dosing, enabled by the fully non-viral approach. P-FVIII-101 can also be combined with Poseida's new proprietary modulator switch, which allows inducible down-regulation to enable patient-specific fine tuning of FVIII levels, which is seen as an important product attribute by the hemophilia community. Development of P-FVIII-101 is ongoing with final optimization of the nanoparticle delivery modality to be validated in NHPs. Title: A Durable Gene Therapy with a Robust AAV-LNP Delivery System Allowing for a Reduced AAV Dose Presenting Author: Jack Rychak, Ph.D., Poseida Therapeutics, Inc. Session Title: AAV Vectors - Preclinical and Proof-of-Concept: Technology Focus Presentation Date/Time: Friday, May 10, 2024, 1:45 - 2:00 PM ET Location: Ballroom 2 Abstract Number: 248 This presentation highlights data from studies exploring the feasibility of combining existing adeno-associated virus delivery vectors (AAVs) with Poseida's piggyBac DNA insertion system. This approach is intended to achieve stable integration of a transgene into a large percentage of hepatocytes for maximal therapeutic benefit, which cannot be readily achieved using an AAV or episomal approach. Pre-clinical data demonstrate exceptional efficacy in mouse models of severe Ornithine Transcarbamylase Deficiency (OTCD). Additionally, robust potency is observed in mouse models of Phenylketonuria (PKU), using low AAV doses, and enabled by the integration of a therapeutic transgene with the SPB transposase. These data highlight the utility of the hybrid platform for enabling effective treatment with lower AAV doses, even in the growing liver early in life. With Poseida's current internal focus on fully non-viral approaches, as announced at the Company's recent R&D Day, the Company may opportunistically consider partnering transactions with respect to its P-PAH-101 and P-OTC-101 programs. Poster Presentations Title: Advanced Gene Editing with an Enhanced Site-Specific Nuclease for Knock-Out and Knock-In Applications Presenting Author: Oscar Alvarez, Ph.D., Poseida Therapeutics, Inc. Session Title: Wednesday Posters: Gene Targeting and Gene Correction New Technologies Session Date/Time: Wednesday, May 8, 2024, 12:00 PM ET Location: Exhibit Hall Abstract Number: 717 Poseida's Cas-CLOVER nuclease system represents a key advancement in gene editing technology with high-fidelity performance that significantly exceeds that of traditional nucleases. Poseida developed its Cas-CLOVER system by incorporating an S44P mutation which confers a two to three-fold improvement in on-target Cas-CLOVER editing efficiency, while fully preserving fidelity and with no increase in off-target editing. The enhanced Cas-CLOVER system exhibits remarkable capabilities for site-specific insertion of genes, as evidenced by the successful integration of a therapeutic transgene in mouse liver cells and associated phenotypical disease rescue in a PKU mouse model. The Company plans to evaluate homology-independent targeting using its rapidly advancing fully non-viral DNA delivery technology for the precise insertion of genes and related gene expression regulators to specific sites in the genome. Title: Optimizing Lipid Nanoparticle Formulations for Enhanced Non-Viral Gene Therapy: Overcoming DNA Delivery Challenges and Achieving High-Efficiency Transgene Integration Presenting Author: George Wang, Ph.D., Poseida Therapeutics, Inc. Session Title: Thursday Posters: Other Nonviral Delivery Session Date/Time: Thursday, May 9, 2024, 12:00 PM ET Location: Exhibit Hall Abstract Number: 1239 This study demonstrates the optimization of DNA delivery to hepatocytes, in vivo, and genomic integration using Poseida's piggyBac DNA insertion system. Poseida has synthesized and evaluated novel terpene-based lipids exhibiting unique DNA encapsulation and delivery properties in vivo. Poseida also identified a class of amphipathic small molecules called Poseida Delivery Excipients (PDEs) with unique capabilities for enhancing DNA delivery. Data demonstrated that inclusion of these PDEs in LNPs improved the insertion of targeted genes and decreased pro-inflammatory cytokine release. LNPs comprising novel ionizable lipids and PDEs also significantly enhanced genomic insertion of therapeutically relevant transgenes in vivo. These unique combinations of LNPs and PDEs could further enhance the potential of Poseida's non-viral DNA platform technology and piggyBac DNA insertion system for treating serious genetic disorders. Title: Novel Biodegradable Lipid Nanoparticles (LNP) for Co-Encapsulation of Complex Nucleic Acid Payloads for In Vivo Genome Editing Presenting Author: Alicia Davis, Ph.D., Poseida Therapeutics Session Title: Friday Posters: Other Nonviral Delivery Session Date/Time: Friday, May 10, 2024, 12:00 PM ET Location: Exhibit Hall Abstract Number: 1737 This presentation highlights the development of an LNP capable of robustly co-encapsulating and delivering Poseida's Cas-CLOVER nuclease system to the liver, while avoiding unintended uptake. Poseida has identified and characterized a novel class of biodegradable ionizable lipids for in vivo mRNA delivery. The Company has identified lipid S, which demonstrated potent mRNA delivery potency and improved clearance from the liver. These studies demonstrate Poseida's discovery chemistry and formulation capabilities to generate high-performing LNPs for the efficient delivery of next-generation genetic medicine platforms such as Cas-CLOVER. About P-KLKB1-101 P-KLKB1-101 is an investigational liver-directed non-viral gene editing approach designed using Cas-CLOVER™ Site-Specific Gene Editing System, Poseida's proprietary high-fidelity nuclease, for site-specific gene editing of the KLKB1 gene, for the treatment of Hereditary Angioedema (HAE). HAE is a rare, inherited disorder that results in the swelling of the skin, intestinal tract, and airways, which can be both debilitating and life-threatening. Preclinical data demonstrate therapeutically relevant reduction of pre-kallikrein levels in both mouse and NHP models. About P-FVIII-101 P-FVIII-101 is an investigational liver-directed gene insertion program combining Poseida's non-viral transposon platform and nanoparticle delivery technologies for the in vivo treatment of Hemophilia A. Hemophilia A is a hereditary bleeding disorder caused by a deficiency in Factor VIII production with a high unmet need, resulting in excessive bleeding occurring either spontaneously or due to trauma and leading to pain and permanent joint damage in patients. P-FVIII-101 utilizes the piggyBac gene integration system delivered via lipid nanoparticle, which has demonstrated the potential to correct Factor VIII deficiency in juvenile and adult animal models using Poseida's fully non-viral insertion system that is capable of whole gene correction. About Poseida Therapeutics, Inc. Poseida Therapeutics is a clinical-stage biopharmaceutical company advancing differentiated allogeneic cell therapies and genetic medicines with the capacity to cure certain cancers and rare diseases. The Company's pipeline includes investigational allogeneic CAR-T cell therapies for both solid tumors and hematologic cancers as well as investigational in vivo genetic medicines that address patient populations with high unmet medical need. The Company's approach is based on its proprietary genetic editing platforms, including its non-viral piggyBac® DNA Delivery System, Cas-CLOVER™ Site-Specific Gene Editing System, Booster Molecule and nanoparticle gene delivery technologies, as well as in-house GMP cell therapy manufacturing. The Company has formed strategic collaborations with Roche and Astellas to unlock the promise of cell therapies for cancer patients. Learn more at and connect with Poseida on X and LinkedIn. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, expected plans with respect to clinical trials, including timing of regulatory submissions and approvals and clinical data updates; anticipated timelines and milestones with respect to the Company's development programs and manufacturing activities and capabilities; the potential capabilities and benefits of the Company's technology platforms and product candidates, including the tolerability and efficacy and safety profile of such product candidates; the quote from Dr. Madison; and the Company's plans and strategy with respect to developing its technologies and product candidates. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon the Company's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, the Company's reliance on third parties for various aspects of its business; risks and uncertainties associated with development and regulatory approval of novel product candidates in the biopharmaceutical industry; the Company's ability to retain key scientific or management personnel; the fact that interim data from the Company's clinical trials may change as more data become available and remain subject to audit and verification procedures that could result in material differences from the final data; and the other risks described in the Company's filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. SOURCE Poseida Therapeutics, Inc.

An overactive enzyme that causes an inherited form of high blood pressure also appears to protect against hypertension-induced cardiac damage. A team of researchers explains how this could fundamentally change the way hearts can be protected from damage. For decades, scientists in Berlin have been researching a strange hereditary condition that results in half the members of certain families having unusually short fingers and extremely high blood pressure. If left untreated, the affected patients usually die of a stroke at the age of 50 years. Researchers at the Max Delbrück Center (MDC) in Berlin identified the cause of the disease back in 2015 and were able to prove their hypothesis five years later using animal models: a mutation in the phosphodiesterase 3A gene (PDE3A) causes its encoded enzyme to become overactive, affecting bone growth and causing blood vessel hyperplasia -- resulting in elevated blood pressure. Immune to hypertension-related damage "High blood pressure almost always leads to the heart becoming weaker," says Dr. Enno Klußmann, head of the Anchored Signaling Lab at the Max Delbrück Center and a scientist at the German Centre for Cardiovascular Research (DZHK). As it has to pump against a higher pressure, Klußmann explains, the organ tries to strengthen its left ventricle. "But ultimately, this results in the thickening of the heart muscle -- known as cardiac hypertrophy -- which can lead to heart failure greatly decreasing its pumping capacity." But in the hypertension patients with the shortened fingers and mutated PDE3A gene, this doesn't happen. "For reasons that are now partly -- but not yet fully -- understood, their hearts appear immune to the damage that usually results from high blood pressure," says Klußmann. The study, which has been published in the journal Circulation, is the result of a collaboration between researchers at the Max Delbrück Center, Charité -- Universitätsmedizin Berlin, and the DZHK. In addition to Klußmann, professors Norbert Hübner and Michael Bader from the Max Delbrück Center were involved as final authors, along with Dr. Sylvia Bähring from the Experimental and Clinical Research Center (ECRC) -- a joint institution of Charité and the Max Delbrück Center. Together with 43 other researchers from Berlin, Bochum, Heidelberg, Kassel, Limburg, Lübeck, Canada, and New Zealand, the team has now reported its findings on the protective effects of the gene mutation -- and why these results could change the way heart failure is treated in the future. The publication has four first authors, three of whom conduct research at the Max Delbrück Center and one at the ECRC. Two mutations with the same effect The scientists performed their tests on human patients with hypertension and brachydactyly (HTNB) syndrome -- i.e., high blood pressure and abnormally short digits -- as well as on rat models and heart muscle cells. The cells were grown from specially engineered stem cells known as induced pluripotent stem cells. Before testing began, researchers altered the PDE3A gene in the cells and the animals to mimic HTNB mutations. "We came across a previously unknown PDE3A gene mutation in the patients we examined," reports Bähring. "Previous studies had always shown the mutation in the enzyme to be located outside the catalytic domain -- but we have now found a mutation right in the center of this domain." Surprisingly, both mutations have the same effect in that they make the enzyme more active than usual. This hyperactivity ramps up the degradation of one of the cell's important signaling molecules known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of the heart muscle cells. "It is possible that this gene modification -- regardless of its location -- causes two or more PDE3A molecules to cluster together and thus work more effectively," Bähring suspects. The proteins stay the same The researchers used a rat model -- created with CRISPR-Cas9 technology by Michael Bader's lab at the Max Delbrück Center -- to try to better understand the effects of the mutations. "We treated the animals with the agent isoproterenol, a so-called beta-receptor agonist," says Klußmann. Such medications are sometimes used in patients with end-stage heart failure. Isoproterenol is known to induce cardiac hypertrophy. "Yet surprisingly, this occurred in the gene-modified rats in a manner similar to what we observed in the wild-type animals. Contrary to what we expected, the existing hypertension did not aggravate the situation," reports Klußmann. "Their hearts were quite obviously protected from this effect of the isoproterenol." In further experiments, the team investigated whether proteins in a specific signaling cascade of the heart muscle cells changed as a result of the mutation and if so which ones. Through this chain of chemical reactions, the heart responds to adrenaline and beats faster in response to situations such as excitement. Adrenaline activates the cells' beta receptors, causing them to produce more cAMP. PDE3A and other PDEs stop the process by chemically altering cAMP. "However, we found little difference between mutant and wild-type rats at both the protein and the RNA levels," Klußmann says. More calcium in the cytosol The conversion of cAMP by PDE3A does not occur just anywhere in the heart muscle cell, but near a tubular membrane system that stores calcium ions. A release of these ions into the cytosol of the cell triggers muscle contraction, thus making the heart beat. After the contraction, the calcium is pumped back into storage by a protein complex. This process is also regulated locally by PDE. Klußmann and his team hypothesized that because these enzymes are hyperactive in the local region around the calcium pump, there should be less cAMP -- which would inhibit the pump's activity. "In the gene-modified heart muscle cells, we actually showed that the calcium ions remain in the cytosol longer than usual," says Dr. Maria Ercu, a member of Klußmann's lab and one of the study's four first authors. "This could increase the contractile force of the cells." Activating instead of inhibiting "PDE3 inhibitors are currently in use for acute heart failure treatment to increase cAMP levels," Klußmann explains. Regular therapy with these drugs would rapidly sap the heart muscle's strength. "Our findings now suggest that not the inhibition of PDE3, but -- on the contrary -- the selective activation of PDE3A may be a new and vastly improved approach for preventing and treating hypertension-induced cardiac damage like hypertrophic cardiomyopathy and heart failure," Klußmann says. But before that can happen, he says, more light needs to be shed on the protective effects of the mutation. "We have observed that PDE3A not only becomes more active, but also that its concentration in heart muscle cells decreases," the researcher reports, adding that it is possible that the former can be explained by oligomerization -- a mechanism that involves at least two enzyme molecules working together. "In this case," says Klußmann, "we could probably develop strategies that artificially initiate local oligomerization -- thus mimicking the protective effect for the heart."