X-Linked Sideroblastic Anemia

New model and vector could be instrumental in transforming the lives of XLSA patients and those with a broad spectrum of other diseases PHILADELPHIA, Jan. 2, 2025 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania Perelman School of Medicine pioneered a first of its kind gene therapy model that offers a potential breakthrough in treating X-linked sideroblastic anemia (XLSA), a rare congenital anemia caused by mutations in the ALAS2 gene crucial for the synthesis of heme, a key compound in hemoglobin. This study marks the first time researchers studied gene therapy to treat this disease, which the authors underscore could have an impact on a broad spectrum of diseases. The research was published today and featured on the cover of the journal Blood. XLSA has traditionally impacted men under the age of 40, however, researchers noted that new cases of girls and mid-life women with the rare disease are beginning to emerge. Patients with XLSA experience a disruption in heme synthesis, leading to a spectrum of issues such as severe anemia and iron overload, which can cause symptoms like extreme fatigue, shortness of breath and growth delays. Most XLSA patients are dependent on pyridoxine supplements, which provide vitamin B6, and blood transfusions to treat the disease. The sole potential cure for XLSA is currently an allogenic stem cell transplant, which is only an option for a limited number of patients due to the need for a compatible donor, high cost and intense chemotherapy involved, which can have significant side effects. In this study, researchers used a newly created preclinical model to evaluate for the first time whether gene therapy could offer a potentially transformative treatment for these patients. Carlo Castruccio Castracani, PharmD, PhD, the study's lead author and the team's Clinical Research Study Manager, used a targeted lipid nanoparticle (LNP) platform technology, established by Hamideh Parhiz, PharmD, PhD, a co-senior study author and Assistant Professor of Pharmacology at Penn Medicine, to induce the deletion of the Alas2 gene in hematopoietic stem cells. Upon deletion of the ALAS2 gene, the researchers subsequently observed classic symptoms of XLSA like anemia and enlargement of the spleen. The model also allowed the researchers to note features of this disease that are significant in humans, such as ring sideroblasts, a type of immature red blood cell. "The lack of ALAS2 in the preclinical model was associated with an expansion in the number of premature red cells, with a high proportion undergoing cell death," said Castruccio Castracani. "We also observed defects in metabolism and mitochondria structure and performance, which prevented healthy red cells from forming and led to severe anemia." Castruccio Castracani and his team developed a lentiviral vector that activated the human ALAS2 gene in erythroid cells, or cells that serve as precursors to normal red blood cells. They found that this gene therapy approach significantly boosted hemoglobin and red blood cell levels, helping normalize hormone levels that control red blood cell production. Preclinical trial subjects that received optimal doses of the vector showed significant improvements in hemoglobin levels, spleen health, and iron balance. "This new model and vector may hold the keys to transforming the lives of XLSA patients," said Stefano Rivella, PhD, a senior author, the Kwame Ohene-Frempong Endowed Chair in Pediatric Hematology research and a faculty member in the Division of Hematology at CHOP. "In future studies, we aim to adapt this model to investigate pharmacological treatment and in vivo gene editing for a broader range of diseases." Castruccio Castracani et al. "An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA." Blood. January 2, 2025. DOI: 10.1182/blood.2024025846. 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 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 the Middleman Family Pavilion and its 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 WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Silence Therapeutics Achieves Another Research Milestone Payment from Mallinckrodt Collaboration for Complement-Mediated Diseases 28 April 2021 LONDON, Silence Therapeutics plc, AIM: SLN and Nasdaq: SLN (“Silence” or “the Company”), a leader in the discovery, development and delivery of novel short interfering ribonucleic acid (siRNA) therapeutics for the treatment of diseases with significant unmet medical need, today announced that it has achieved another research milestone as part of its ongoing RNAi collaboration with Mallinckrodt plc (“Mallinckrodt”) for complement-mediated diseases, triggering a further $2.0 million payment to Silence. The milestone relates to pre-clinical development work on the SLN500 C3 targeting program, highlighting the successful ongoing collaboration between the two companies. Silence continues to work with Mallinckrodt to progress Investigational New Drug (IND) enabling studies for SLN501, the first nominated product candidate in the SLN500 program, this year. The collaboration with Mallinckrodt is focused on the development and commercialization of RNAi therapeutics designed to inhibit or ‘silence’ the complement cascade, a group of proteins involved in the immune system and which play a role in the development of inflammation. Using Silence’s proprietary mRNAi GOLD™ platform, siRNAs engineered to inhibit each target in the collaboration will be optimized and investigated before progressing into clinical development. In July 2019, Silence received an upfront payment of $20 million from Mallinckrodt for an exclusive worldwide license to siRNAs against one complement target, C3, and options to license siRNAs against up to two additional targets, each of which Mallinckrodt has exercised at $2 million per target. Under the terms of the agreement, Silence is responsible for preclinical activities and for executing development of each target through Phase 1, after which Mallinckrodt will assume responsibility for clinical development and global commercialization. Silence is also eligible to receive tiered double-digit royalties on net sales for each product candidate and up to $2 billion in total milestone payments across all three targets. Enquiries: About Silence TherapeuticsSilence Therapeutics is developing a new generation of medicines by harnessing the body's natural mechanism of RNA interference, or RNAi, to inhibit the expression of specific target genes thought to play a role in the pathology of diseases with significant unmet medical need. Silence's proprietary mRNAi GOLD™ platform can be used to create siRNAs that precisely target and silence disease-associated genes in the liver, which represents a substantial opportunity. Silence's wholly owned product candidates include SLN360 designed to address the high and prevalent unmet medical need in reducing cardiovascular risk in people born with high levels of lipoprotein(a) and SLN124 designed to address iron loading anemias. Silence also maintains ongoing research and development collaborations with AstraZeneca, Mallinckrodt Pharmaceuticals, and Takeda, among others. For more information, please visit . About Mallinckrodt Mallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit . Forward-Looking StatementsCertain statements made in this announcement are forward-looking statements, including with respect to the Company’s clinical and commercial prospects. These forward-looking statements are not historical facts but rather are based on the Company's current expectations, estimates, and projections about its industry; its beliefs; and assumptions.  Words such as 'anticipates,' 'expects,' 'intends,' 'plans,' 'believes,' 'seeks,' 'estimates,' and similar expressions are intended to identify forward-looking statements. These statements are not guarantees of future performance and are subject to known and unknown risks, uncertainties, and other factors, some of which are beyond the Company's control, are difficult to predict, and could cause actual results to differ materially from those expressed or forecasted in the forward-looking statements. The Company cautions security holders and prospective security holders not to place undue reliance on these forward-looking statements, which reflect the view of the Company only as of the date of this announcement. The forward-looking statements made in this announcement relate only to events as of the date on which the statements are made. The Company will not undertake any obligation to release publicly any revisions or updates to these forward-looking statements to reflect events, circumstances, or unanticipated events occurring after the date of this announcement except as required by law or by any appropriate regulatory authority.

Silence Therapeutics to Participate in March Investor Conferences 22 February 2021 LONDON, Silence Therapeutics plc, AIM: SLN and Nasdaq: SLN (“Silence” or “the Company”), a leader in the discovery, development and delivery of novel short interfering ribonucleic acid (siRNA) therapeutics for the treatment of diseases with significant unmet medical need, today announced that Company management will present business updates at two virtual investor conferences in March, details of which can be found below: Cowen 41st Annual Health Care Conference H.C. Wainwright Global Life Sciences Conference Live webcasts of the presentations can be accessed via the Investors section of the Company's website at . An archived replay of the webcasts will be available on the Company's website following the conference. Enquiries: About Silence Therapeutics Silence Therapeutics is developing a new generation of medicines by harnessing the body's natural mechanism of RNA interference, or RNAi, to inhibit the expression of specific target genes thought to play a role in the pathology of diseases with significant unmet medical need. Silence's proprietary messenger RNAi GOLD™ (GalNAc Oligonucleotide Discovery) Platform can be used to create siRNAs that precisely target and silence disease-associated genes in the liver, which represents a substantial opportunity. Silence's wholly owned product candidates include SLN360 designed to address the high and prevalent unmet medical need in reducing cardiovascular risk in people born with high levels of lipoprotein(a) and SLN124 designed to address iron loading anemias. Silence also maintains ongoing research and development collaborations with AstraZeneca, Mallinckrodt Pharmaceuticals, and Takeda, among others. For more information, please visit .