Fig. 5A. GTG-banded partial metaphase of boy with Ochoa syndrome...
Iron Overload Associated With Elevated Fracture Risk
Iron overload is associated with increased risk for fracture, published in the Journal of Clinical Endocrinology and Metabolism.
Hereditary hemochromatosis, thalassemia major, and sickle cell anemia are associated with higher iron accumulation and poor bone mineral density. However, the effects of iron overload on fracture risk are not well understood.
Investigators from ETH Zurich in Switzerland and Technische Universität Dresden in Germany conducted a population-based cohort study using data from the IQVIA medical research database which is a longitudinal cohort comprising more than 800 general practices in the United Kingdom. Patients (n=20,264) with iron overload or an incident diagnosis of thalassemia major, sickle cell disease, or hemochromatosis were matched with up to 10 control participants (n=192,956).
The primary outcome was first occurrence of osteoporotic fracture of the humerus, forearm, vertebra, or hip. Iron overload was defined as ferritin over 1000 mg/L.
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[P]atients with iron overload have a 55% increased risk for fracture, particularly for clinical vertebral and humerus fractures where the risk almost doubled when compared to matched patients without iron overload.
The iron overload and control cohorts comprised 39.1% and 42.3% women and had mean (SD) ages of 57.8 (17.5) and 57.7 (18.3) years, BMIs of 27.1 (5.9) and 27.3 (5.7) kg/m2, and ferritin levels of 1731.4 (1440.4) and 141.1 (222.4) mg/L, respectively.
Among patients with iron overload, 6754 were diagnosed with thalassemia major, sickle cell disease, or hemochromatosis.
During a mean follow-up between 4.2 and 4.7 years, 775 patients with iron overload and 3757 control patients had a fracture, corresponding with fracture incidence rates (IRs) of 8.26 and 4.72 per 1000 person-years (py), respectively.
In the adjusted analysis, iron overload was associated with increased risk for:
Stratified by type of iron overload, patients with elevated ferritin had a higher fracture IR (11.60 per 1000 py) than patients with qualifying diagnoses (4.27 per 1000 py). Overall, elevated ferritin was associated with higher risk for fracture than specific diagnoses (aHR, 1.57; 95% CI, 1.31-1.88).
Among male patients, elevated ferritin was associated with risk for any fracture (aHR, 2.11; 95% CI, 1.82-2.44), humerus fracture (aHR, 2.71; 95% CI, 2.00-3.66), vertebral fracture (aHR, 2.45; 95% CI, 1.79-3.36), hip fracture (aHR, 1.85; 95% CI, 1.46-2.33), and forearm fracture (aHR, 1.67; 95% CI, 1.16-2.41), whereas eligible diagnoses were not associated with elevated risk.
Among female patients, elevated ferritin was associated with risk for any fracture (aHR, 1.93; 95% CI, 1.68-2.11), vertebral fracture (aHR, 2.75; 95% CI, 2.02-3.75), humerus fracture (aHR, 2.41; 95% CI, 1.82-3.20), and hip fracture (aHR, 1.86; 95% CI, 1.49-2.32) and eligible diagnoses were associated with elevated risk for humerus fracture (aHR, 1.48; 95% CI, 1.03-2.12).
Study limitations include the availability of data on ferritin levels for 2.9% of control patients, which could indicate misclassification of some control patients.
The study authors concluded, "[P]atients with iron overload have a 55% increased risk for fracture, particularly for clinical vertebral and humerus fractures where the risk almost doubled when compared to matched patients without iron overload."
This article originally appeared on Endocrinology Advisor
Orna, Vertex Partner On Gene-editing Therapies For SCD, TDT
Orna Therapeutics is partnering with Vertex Pharmaceuticals to develop gene-editing therapies for people with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).
The three-year collaboration will leverage Orna's proprietary lipid nanoparticle (LNP) delivery system. LNPs are tiny vesicles made up of fatty molecules that can be used to deliver gene editing machinery to a patient's hematopoietic stem cells, which can give rise to all types of blood cells.
The agreement "validates our industry leading extra-hepatic LNP delivery chemistries and highlights the importance of delivery to enable the next wave of RNA medicines," Amit Munshi, Orna's CEO, said in a company press release.
SCD and TDT are diseases that affect hemoglobin, the protein that red blood cells use to carry oxygen throughout the body. SCD is caused by mutations in the HBB gene that lead to the production of a faulty version of hemoglobin, whereas in TDT hemoglobin levels are low or the protein is missing.
In either case, patients may develop anemia, a condition caused by a shortage of red blood cells in the blood, impairing oxygen delivery throughout the body.
In vivo therapiesVertex, along with CRISPR Therapeutics, has developed a gene-editing therapy called Casgevy (exagamglogene autotemcel), which is approved by the U.S. Food and Drug Administration to treat SCD and TDT. Casgevy was the first approved therapy to employ the CRISPR/Cas9 gene-editing technology.
Casgevy is a so-called ex vivo therapy, meaning gene editing occurs outside the body after stem cells are harvested from the patient. In contrast, Orna's LNPs are designed to deliver gene-editing components directly to cells within the patient's body. This approach could enable the development of in vivo therapies, in which gene editing occurs inside the body without the need for harvesting or transplanting cells.
"We are excited to collaborate with [Vertex] to develop in vivo therapies that leverage our proprietary technologies to achieve unprecedented delivery to [hematopoietic stem cells]," Munshi said.
When undergoing treatment with Casgevy, a patient's hematopoietic stem cells are collected and modified in the lab to produce high levels of fetal hemoglobin, a form of the protein normally produced during fetal development that is more effective at transporting oxygen than the adult form.
After a round of chemotherapy used to destroy faulty stem cells, the modified stem cells are transplanted back to the patient. They are then expected to give rise to new red blood cells that are capable of producing fetal hemoglobin.
Under the terms of the agreement, Orna will receive an upfront payment of $65 million and is eligible to receive up to $635 million according to the achievement of pre-specified research, preclinical, regulatory, and commercial milestones related to developed therapies.
Orna will also be eligible to receive tiered royalties on future net sales of treatments that may result from this collaboration and may receive up to $365 million in additional milestones per product, if Vertex uses its technology for additional indications.
The agreement "has the potential to deliver large-scale impact to patients," said Ansbert Gadicke, MD, Orna's chairman and managing partner of MPM BioImpact, a biotechnology investment company.
Allo-SCT Improves Lives Of Children With Sickle Cell Anemia & Abnormal Cerebral Artery Velocities
Photo Credit: Silver Place
Allogeneic stem cell transplantation (allo-SCT) was more efficacious than standard of care in pediatric patients with sickle cell anemia who had a history of abnormal cerebral artery velocities. Allo-SCT was associated with reduced hospitalization and vaso-occlusive crises, and an improved QOL after 10 years of follow-up.
The observational DREPAGREFFE-2 trial (NCT05053932) assessed 67 pediatric patients between 5 and 15 years of age with sickle cell anemia and a history of abnormal cerebral artery velocities1. All patients had at least one sibling without sickle cell anemia. The 32 patients with a matched sibling donor received a transplant, while the other 35 were maintained on chronic transfusion. If patients in the 'chronic transfusion' group reached normalized velocities and did not have stenosis, they were switched to hydroxyurea.
After 10 years of follow-up, the mean number of hospitalizations was 0.2 in the allo-SCT group and 6.1 in the standard-of-care group (P<0.001). Also, the mean number of vaso-occlusive crises was lower in the allo-SCT group than in the standard of care group (0.0% vs 3.8%; P=0.001). Francoise Bernaudin, MD, from the Center Hospitalier Intercommunal Creteil, in France, added that patients who switched to hydroxyurea had worse outcomes after hospitalization or vaso-occlusive crises than patients who remained on chronic transfusion. "Next, patients in the allo-SCT arm had significantly better functioning at school, physical functioning, and even social functioning than patients on standard of care," mentioned Dr. Bernaudin. Finally, patients who were stroke-free at baseline (n=60) benefited from allo-SCT in terms of reduced intracranial stenosis, decreased ischemic lesions, and enhanced cognitive performance.
"In children with sickle cell anemia and a history of abnormal cerebral artery velocities, allo-SCT was more efficacious than standard of care across various important outcomes," concluded Dr. Bernaudin. "Early allo-SCT is useful in patients with sickle cell anemia and matched sibling donors in case they have abnormal cerebral artery velocities, severe baseline hemolytic anemia, crises, or complications despite hydroxyurea treatment. In patients without matched sibling donors, haplo-identical SCT or gene therapy should be considered in case of persistent/worsening cerebral vasculopathy or disease progression, respectively."
Medical writing support was provided by Robert van den Heuvel.
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