SMPD2

--Researchers found exposing cells to a small molecule drug improved their fitness during hematopoietic stem cell transplants, which could broaden access and improve outcomes for ex vivo gene therapy– PHILADELPHIA, Sept. 27, 2023 /PRNewswire/ -- A readily available, inexpensive small molecule drug can improve the fitness of hematopoietic stem and progenitor cells (HSPCs) that are modified outside of the body, potentially improving the success of procedures like ex vivo gene therapy, according to a new study by researchers at Children's Hospital of Philadelphia (CHOP). The study, published in the journal Blood, showed that targeting components in the cells called extracellular vesicles (EVs) relieves the stress on cells when outside of the body, improving their performance when they are transplanted back inside. "We initially embarked on this project to better understand the role of these vesicles, assuming – wrongly, as it turns out – that blocking their function would have detrimental effects on the cells," said first author Stephanie Hurwitz, MD, PhD, a research fellow in the Kurre Lab at CHOP and Hematopathologist at the University of Pennsylvania. "We discovered the opposite is true: blocking the formation of these vesicles over a relatively short period of time actually improved the cells' fitness, initiating an adaptive stress response that protects them from the stress of being outside of the body. Ultimately, this serendipitous finding could enhance the quality of transplant products used in treatments like ex vivo gene therapy, improving patient outcomes." Hematopoietic stem cell transplantation (HSCT) involves the transfer of HSPCs from a donor to patients with both benign and malignant diseases. In some cases, as in ex vivo gene therapy, the patient acts as their own donor: the patient's HSPCs are removed, modified outside of the body using gene addition or gene editing, and then transplanted back in. When enough cells are available for modification, this strategy has proven to be a powerful platform for treating genetic blood disorders, including sickle cell disease and beta thalassemia. However, maintaining the fitness of these cells outside of the body poses a challenge, and any loss of fitness introduces the risk that the cells will not properly restore the blood and immune cell system in patients. For this reason, researchers have sought to better understand HSPC programming and signaling so that every attempt could be made to maintain cell health ahead of transplant. One process that we now learn contributes to cell equilibrium is the secretion of EVs, which are important for delivering messages from cell to cell and maintaining proper cell function. However, technical challenges have previously prevented researchers from fully understanding the role these EVs might play in HSPC fitness outside of the body. To explore the role of EVs, the researchers exposed both mouse and human HSPCs to GW4869, a readily available small molecule drug that blocks neutral sphingomyelinase-2 (nSMase2), an enzyme involved in EV formation. The researchers found that an exposure of 24 hours led to sustained improvements in cell fitness and transplantation efficiency after ex vivo culture, with improved rates of blood cell function in mouse models. Additionally, the researchers found that blocking nSMase2 in human CD34+ cells leveled disparities in how well the cells of varying HLA types performed after transplantation into mice. This is of particular interest given important role of HLA in long-term transplantation outcomes. Drilling down on the mechanisms behind these phenomena, the researchers determined that blocking nSMase2 activates an integrated stress response, effectively putting the cells into a state of quiescence, where they are protected from external stressors. This occurs due, in part, from GW4869 disrupting sphingolipid metabolism, which impairs the release of nSMase2-dependent EVs. "While numerous advances have been made over past decades to improve safety and efficiency of HSPC transplantation and ex vivo gene therapy, constraints in cell quantity and graft success continue to limit outcomes," said senior author Peter Kurre, MD, Director of the Pediatric Comprehensive Bone Marrow Failure Center at CHOP. "This important study, which links EV trafficking and the integrated stress response as a regulatory dyad guarding HSPC integrity and long-term fitness, has important implications for potentially broadening patient eligibility to ex vivo gene therapies. Researchers should continue to explore the potential of this small molecule drug in improving ex vivo HSPC culture and transplantation." This research was supported by NIH grants R01-HL164633, 4-R38-HL143613-04 , T32 HL-07439, and P30ES013508. The analyses were made possible through collaboration with the CHOP Flow Cytometry core laboratory, CHOP Department of Veterinary Resources, University of Pennsylvania Stem Cell and Xenograft Core, University of Pennsylvania Hematopoietic Stem Cell Laboratory, CHOP-PENN Proteomics Core Facility, and CHOP Center for Applied Genomics core laboratory. Hurwitz et al. "Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response," Blood, online Sept. 12, 2023, DOI: 10.1182/blood.2023022147 About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as an inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (267) 426-6084 [email protected] SOURCE Children's Hospital of Philadelphia

It’s a big day for Sanofi as the pharmaceutical giant welcomes two European drug approvals, both for rare enzyme deficiencies. One regulatory nod ushers in the first treatment in Europe for a particular disease. The other covers a successor to a blockbuster Sanofi drug—though that approval does not go as far as the drugmaker had hoped. Sanofi announced Tuesday that the European Commission approved olupdase alfa, making it the first treatment authorized in Europe for acid sphingomyelinase deficiency (ASMD). Sometimes referred to as Niemann-Pick disease, the disorder leads to lipid buildup in body tissues that causes complications in various organs. The inherited enzyme deficiency is categorized according to the underlying genetic mutation. The European approval covers the treatment of children and adults with ASMD type A/B or ASMD type B. Olupdase alfa, which is branded as Xenpoyzme, is an engineered version of the sphingomyelinase enzyme that is either deficient or defective in ASMD patients. Approval of the enzyme replacement therapy is based on the results of two clinical trials, one in children and the other in adults. Results of the placebo-controlled adult study showed that treatment with Xenpozyme improved lung function and reduced spleen size after 52 weeks, meeting the main goals of the clinical trial. The open-label pediatric study showed improvement from baseline in the measures of lung function and spleen size after one year of treatment. Regulatory approval does not cover ASMD that has manifest in the central nervous system, which was not tested in clinical trials. Xenpoyzme has also not been tested in patients with ASMD type A. The intravenously infused therapy was well tolerated by patients. The most common adverse effects reported in the adult study included headache, an inflammatory attack of the pharynx and nasal cavities, upper respiratory tract infection, cough, and joint stiffness. In the pediatric study, adverse effects deemed serious were reported in three patients. One patient had two transient cases of elevated liver enzymes, which can be a sign of drug toxicity. Another patient had a case of hives and rash. The third patient had an anaphylactic reaction. No patients permanently discontinued treatment due to an adverse effect. “The ASMD community has waited many years for a treatment for this rare and debilitating genetic disease,” John Reed, Sanofi executive vice president and global head of research and development said in a prepared statement. “The approval of Xenpozyme by the European Commission represents a transformational shift in what we can offer to patients, demonstrated by the clinically important improvements across major manifestations of ASMD and the sustained effects noted over longer-term treatment.” The European approval of Xenpozyme is the drug’s second regulatory nod. Authorities in Japan approved the enzyme replacement therapy in March. The FDA is still reviewing Xenpozyme and is expected to issue a regulatory decision by October. The second Sanofi drug approval announced Tuesday is for avalglucosidase alfa, a treatment for Pompe disease. This enzyme replacement therapy was approved by the FDA last summer. In the U.S., the drug is marketed as Nexviazyme. In Europe, it will be branded as Nexviadyme. In Pompe disease, patients have low levels of an enzyme called acid alpha-glucosidase. This enzyme is needed to break down glycogen stored in muscle tissue. The inherited disorder leads to skeletal and cardiac muscles damage, which manifests as muscle weakness and breathing difficulty. For years, standard Pompe treatment was a Sanofi enzyme replacement therapy called Lumizyme (marketed in Europe as Myozyme), a product that topped €1 billion (about $1.05 billion) in revenue last year. Nexviadyme is also an enzyme replacement therapy. But compared to Myozyme, the new Sanofi Pompe treatment is designed to target a particular receptor that is key for the way that cells take in the therapy. Increased cellular uptake of the enzyme replacement is intended to improve the clearance of glycogen. The Phase 3 test of Nexviadyme compared that therapy to its predecessor. Sanofi reported that patients treated with Nexviadyme showed a 2.9% improvement from baseline in a measure of lung function, which was the main goal. While that improvement more than enough to show that Nexviadyme was roughly comparable to Myozyme, it was just shy of the change needed to demonstrate statistical superiority. A six-minute walk test was one of the secondary goals of the study. Patients treated with Nexviadyme were able to walk 32.2 meters farther compared to baseline. That’s 30 meters farther than the change reported in patients treated with Myozyme. European approval of Nexviadyme covers both late-onset and and infantile onset Pompe disease. While the drug is new, it is apparently not novel enough. The European Commission did not recognize the therapy as a “new active substance” and an “orphan medicinal product,” designations that would have conferred 10 years of marketing exclusivity upon the drug’s approval. The FDA’s approval came with orphan drug designation, which gives the product seven years of marketing exclusivity in the U.S. Despite failing to win comparable status in Europe, Sanofi said it is positioning Nexviadyme as a new standard of care for Pompe treatment.