Publications by authors named "Kaczmarek R"

Adeno-associated virus-based gene therapy for hemophilia has emerged as a revolutionary treatment option, offering potential correction of clotting factor deficiency through a single intravenous infusion of functional genes directed to hepatocytes. With 3 gene therapies recently approved, this approach shows promise in transforming the lives of individuals with hemophilia. However, the complexity of gene therapy and the lack of standardization of methods in different components of this therapy can lead to unique challenges for clinical implementation.

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Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.

Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.

Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE.

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Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact.

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Article Synopsis
  • Human Gb3/CD77 synthase, an enzyme, creates Galα1→4Gal structures on glycosphingolipids and glycoproteins, which are important for bacterial recognition in infections.
  • The major product, Globotriaosylceramide (Gb3), acts as a receptor for harmful toxins from certain bacteria and is also linked to symptoms of Anderson-Fabry disease due to enzyme deficiency.
  • Additionally, the synthase is implicated in cancer biology, playing a role in cancer cell survival and resistance to treatments, and influencing the P1PK blood group system.
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Background: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited.

Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B.

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We present a case of bilateral endogenous endophthalmitis with an extremely rare etiology of . A 42-year-old asplenic patient with bilateral deterioration of visual acuity presented to the Emergency Department. The sudden deterioration of visual acuity, which prompted the patient to visit the ophthalmologist, was the first sign of the onset of sepsis.

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Gene therapy for severe hemophilia A uses an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in factor VIII (FVIII) activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy.

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: Endotamponade of the vitreous body with silicone oil is a common procedure, being the basis of many vitreoretinal surgeries. However, emulsification may happen, which is a clinically relevant adverse event of silicone oil use. : This review provides a thorough analysis of the emulsification process.

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Article Synopsis
  • - After years of development, gene therapies for hemophilia A and B have been commercialized, effectively normalizing factor levels in some patients but demonstrating variable long-term efficacy.
  • - Clinical trials reveal issues such as liver toxicities and potential oncogenicity of AAV vectors, which complicate their long-term safety and efficacy, alongside the challenge of immune responses limiting the possibility for repeat dosing.
  • - While AAV gene therapies present new treatment options, they are not universal cures, necessitating the development of alternative gene transfer systems to address efficacy variability and improve access for ineligible patients.
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  • Independent data collection is essential for effectively addressing the safety and efficacy challenges of gene therapy in hemophilia, as it allows for careful monitoring of patient outcomes.
  • The Gene Therapy Minimum Data Set (GT-MDS) establishes a standardized approach to gather critical safety and efficacy information, ensuring that key data points are consistently collected for all treated patients.
  • Developed by several organizations including the World Federation of Hemophilia, the GT-MDS facilitates rapid evaluation of gene therapy results while maintaining a focus on essential information across a global registry.
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Background: Factor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy.

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Background: Clotting factor concentrates have been the mainstay of severe hemophilia treatment over the last 50 years. Differences in risk of neutralizing antibody (inhibitor) formation according to concentrate used remain clinically relevant.

Objectives: To assess inhibitor development according to type of clotting factor concentrate in previously untreated patients (PUPs) with severe hemophilia A and B.

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Adeno-associated virus gene therapy has been the subject of intensive investigation for monogenic disease gene addition therapy for more than 25 years, yet few therapies have been approved by regulatory agencies. Most have not progressed beyond phase 1/2 due to toxicity, lack of efficacy, or both. The liver is a natural target for adeno-associated virus since most serotypes have a high degree of tropism for hepatocytes due to cell surface receptors for the virus and the unique liver sinusoidal geometry facilitating high volumes of blood contact with hepatocyte cell surfaces.

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Introduction: The aim was to detect subclinical structural retinal abnormalities in optical coherence tomography (OCT) in ophthalmologically asymptomatic systemic lupus erythematosus (SLE) patients without signs of lupus retinopathy or drug toxicity in fundus examination and in OCT and to assess the relationship between OCT parameters and disease activity, therapy type and burden on other organs to demonstrate the utility of OCT in early retinal impairment in SLE patients.

Material And Methods: Cross-sectional study. Thirty-three SLE patients (57 eyes) and 31 healthy individuals (56 eyes) were enrolled in the study.

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Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6--tolyl-2'-deoxyribofuranosyl-furo[2,3-]pyrimidin-2-one was determined by X-ray crystallography.

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Article Synopsis
  • * Over the past 50 years, hemophilia treatments have improved survival and quality of life, but there are still challenges in achieving health equity with individuals without the condition.
  • * A careful and informed decision-making process is necessary for those considering gene therapy, highlighting the importance of addressing biases in healthcare and ensuring safety for patients.
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Despite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in ∼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen.

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Background: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.

Methods: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10 vector genomes of valoctocogene roxaparvovec per kilogram of body weight.

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Article Synopsis
  • - The study investigated the use of oral anti-CD3 monoclonal antibodies to prevent the formation of anti-drug antibodies (ADAs) in hemophilia A mice undergoing clotting factor VIII (FVIII) protein replacement therapy.
  • - Administering low-dose oral anti-CD3 F(ab') led to a reduction in neutralizing ADAs, especially when given at the same time as FVIII therapy, with immune tolerance linked to certain populations of CD4 T cells.
  • - Combining oral anti-CD3 treatment with oral FVIII antigen intake did not enhance the suppression of ADAs, indicating that while oral anti-CD3 shows promise, its mechanisms of action are different and not synergistic with the FVIII antigen approach.
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MicroRNAs (miRNAs) are small noncoding RNAs which mediate some of the pathological mechanisms of diabetic retinopathy. The aim of this study was to identify differentially expressed miRNAs in the vitreal exosomes of proliferative diabetic retinopathy (PDR) patients and non-diabetic controls. Exosomes were extracted from the vitreous samples of 10 PDR patients and 10 controls.

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