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Phytanic acid alpha-oxidation. Differential subcellular localization in rat and human tissues and its inhibition by nycodenz.

The subcellular site of oxidation of [1-14C]phytanic acid to pristanic acid and CO2 was examined by measurement of the release of 14CO2 in different organelles from human and rat tissues prepared by isopycnic density gradient centrifugation in Nycodenz. The activity of phytanic acid oxidation in human tissues (liver and cultured skin fibroblasts) paralleled that of the peroxisomal marker catalase. We also observed that Nycodenz (commonly used gradient material for isolation of subcellular organelles) has a strong inhibitory effect on the alpha-oxidation of phytanic acid. This inhibition is rev

Epilepsy in adult X-linked adrenoleucodystrophy due to the deletion c.1415-1416delAG in exon 5 of the ABCD1-gene.

Seizures in cerebral X-linked adrenoleucodystrophy (X-ALD) more frequently occur in the early-onset compared to the late-onset form. Here we describe an adult in whom X-ALD deteriorated after head trauma and who developed epilepsy with progression of X-ALD. In a 50 year-old Caucasian male, cerebral X-ALD was diagnosed upon progressive gait disturbance, intellectual decline, elevated very-long chain fatty acids in the serum or leucocytes, cerebral MRI, showing extensive, symmetric, homogenous demyelination in the parieto-occipital areas, the splenium corporis callosum, the thalamus, the crura c

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, alt

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

Introduction: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central ner … Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive.

Studies on the oxidation of phytanic acid and pristanic acid in human fibroblasts by acylcarnitine analysis.

The alpha-oxidation of phytanic acid and the beta-oxidation of pristanitc acid were investigated in cultured fibroblasts from controls and p … 100), have symptoms from birth on and usually do not live beyond their first year of life. Neonatal adrenoleukodystrophy (N-ALD, McKusick 202370) has a milder presentation, whereas infantile Refsum disease (IRD, McKusick 266510) is the mildest form among the generalized peroxisomal disorders. Not only in these generalized peroxisomal disorders, but also in some isolat …

Биомаркеры нейродегенеративных заболеваний в процессе принятия регламентационных решений Европейским агентством медицины.

ВВЕДЕНИЕ: Биомаркеры (БМ) являются ценными инструментами для содействия ранней диагностике (подтипов) заболеваний, улучшения отбора и стратификации пациентов и выявления терапевтических последствий или проблем безопасности. В этом исследовании рассматривается вопрос о том, в какой степени БМ используются при разработке методов лечения нейродегенеративных заболеваний (НДД), а также темы для обсуждения в отношении БМ в процессе консультирования по вопросам нормативного регулирования и принятия решений и обмена данными, касающимися БМ. МЕТОДЫ: Проверены заявки Европейского агентства по медицине н

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… Abbreviations: ABCD1 , adenosine triphosphate binding cassette subfamily D member 1; Aβ, amyloid‐β; ALD, adrenoleukodystrophy; ALDP, adrenoleukodystrophy protein; ALS, amyotrophic lateral sclerosis; APOE ε4, apolipoprotein E ε4; BM, biomarker; CoU, context of use; CRP, C‐reactive protein; CSF, cerebrospinal … Abbreviations: ABCD1 , adenosine triphosphate binding cassette subfamily D member 1; Aβ, amyloid‐β; ALD, adrenoleukodystrophy; ALDP, adrenoleukodystrophy protein; ALS, amyotrophic lateral sclerosis; APOE ε4, apolipoprotein E ε4; BM, biomarker; CoU, context of use; CRP, C‐reactive protein; CSF, cerebrospinal …

Myelin Displacement and Revention in the Central Nervous System: Молекулярные механизмы, болезни и перспективные терапевтические цели.

Майлин пластичность имеет основополагающее значение для формирования нейронных сетей и оптимизации нейронных функций, формирования схем, регулирующих эмоции, сознание, сенсацию и управление двигателем. Подкомбинированный олигодендроцитами, миелин подвергается пожизненной реконструкции, которая требует высокой метаболической активности; это делает миелин-олигодендроцитную единицу весьма восприимчивой к метаболическому стрессу, старению и патологическим оскорблениям. Хотя обезвоживание является основной характеристикой различных хронических неврологических расстройств, в настоящем обзоре особо п

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… Major leukodystrophy subtypes include X‐linked adrenoleukodystrophy (X‐ALD) [ 186 ], metachromatic leukodystrophy (MLD) [ 187 ], Pelizaeus–Merzbacher disease (PMD) [ 188 ], and Krabbe disease (KD) [ 189 ]. …

Выборочное ингибирование TLR2 стимулирует созревание олигодендроглиевых клеток потомства до олигодендроцитов.

Важно описать новые технологии для преодоления барьера и поощрения ремиелионации, поскольку многие аксоны остаются демиелиномированными в CNS пациентов с множественным склерозом (MS). Недавние исследования показывают, что LR2 является негативным регулятором созревания олигодендроглиевых клеток потомства (OPC) до олигодендроцитов (OLs) и что TLR2 присутствует в хронических повреждениях MS человека. Однако до недавнего времени не существовало конкретного ингибитора TLR2. Поэтому мы создали пептид, соответствующий TLR2-interacting Домена MyD88 (TIDM), которая конкретно препятствует TLR2, но не др

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… Therefore, demyelination is considered as an important pathological hallmark in several neuroinflammatory disorders including MS [ 35 ], Devic’s disease [ 36 ], progressive multifocal leukoencephalopathy [ 37 ], Krabbe disease [ 38 ], neuromyelitis optica [ 39 ], and X-Adrenoleukodystrophy [ 40 , 41 … The changing face of adrenoleukodystrophy . Endocr Rev 2020 ; 41 : 577 – 93 32364223 10.1210/endrev/bnaa013 PMC7286618 41. Pahan K , Khan M , Singh I . Therapy for X-adrenoleukodystrophy: normalization of very long chain fatty acids and inhibition of induction of cytokines by cAMP . …

Gaucher disease: clinical profile and therapeutic developments.

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster.

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… If used for Gaucher disease, as reported for the neurodegenerative disease adrenoleukodystrophy 74 and currently in clinical trials for presymptomatic metachromatic leukodystrophy in infants and children, such an approach would have the advantage of being a one-off procedure requiring less powerful myelo-ablative … Cartier N Hacein-Bey-Abina S Bartholomae CC Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy Science 2009 326 5954 818 823 19892975 10.1126/science.1171242 75. …

Current State of Human Gene Therapy: Approved Products and Vectors.

In the realm of gene therapy, a pivotal moment arrived with Paul Berg's groundbreaking identification of the first recombinant DNA in 1972. This achievement set the stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and a host of other ailments, are now being addressed at their root cause-the genetic level. Presently, the gene therapy landscape stands adorned with 22 approved in vivo and ex vivo products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, and many more. In this comprehensive exploration, we delve into a rich ass

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… , atherosclerotic peripheral arterial disease, critical limb ischemia, nasopharyngeal cancer, SOS/VOD with multiorgan dysfunction, bacillus Calmette–Guérin (BCG)-unresponsive non-muscle invasive bladder cancer, hemophilia B, aromatic L-amino acid decarboxylase deficiency, multiple myeloma, cerebral adrenoleukodystrophy …

The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases,

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… Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N. Engl. J. Med. 2017;377:1630–1638. doi: 10.1056/NEJMoa1700554. 68. Gupta A.O., Raymond G., Pierpont E.I., Kemp S., McIvor R.S., Rayannavar A., Miller B., Lund T.C., Orchard P.J. … Treatment of cerebral adrenoleukodystrophy: Allogeneic transplantation and lentiviral gene therapy. Exp. Opin. Biol. Ther. 2022;22:1151–1162. doi: 10.1080/14712598.2022.2124857. 69. Brunson A., Keegan T.H.M., Bang H., Mahajan A., Paulukonis S., Wun T. …

Evidence for the use of intravenous immunoglobulins--a review of the literature.

Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel

Cell therapies in the clinic.

Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated

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… protein | Autologous | Cerebral adrenoleukodystrophy | Elivaldogene autotemcel (bluebird bio) | IV | NCT03852498 (Phase 3) | NCT01896102 (Phase 2/3); Lenti‐D lentiviral vector encoding cDNA for human adrenoleukodystrophy protein Yes | HSC | CD18 | Autologous | Leukocyte adhesion deficiency | RP‐L201 … While most of the trials (95%) are still in Phase 1 or 2 (Figure 4(a) (ii)), there is one trial in Phase 3, where elivaldogene autotemcel, a therapy that uses GM HSCs endowed with functional human adrenoleukodystrophy protein, is used to treat cerebral adrenoleukodystrophy ( NCT03852498 ). …

Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence.

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled "Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence". The event brought together a diverse group of experts, including international regulatory bodies, regulated industries, healthcare professionals, patients, academic researchers and global health advocates, to discuss the rapid advancements in gene therapy and the pressing need for equitable access in low-and middle-

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… A range of FDA-approved gene therapies have become available to patients, addressing conditions such as spinal muscular atrophy (SMA), hemophilia, adrenoleukodystrophy and SCD ( Table 1 ) [ 3 ]. … Product Name | Indication | Type of Gene Therapy Zolgensma | Spinal Muscle Atrophy | In vivo Luxturna | Inherited Retinal Disease | In vivo Skysona | Adrenoleukodystrophy | Ex vivo—gene addition Zynteglo | Transfusion-dependent Thalassemia | Ex vivo—gene addition Hemegenix | Hemophilia B | In vivo Elevidys …

Clinical development of gene therapy: results and lessons from recent successes.

Therapeutic gene transfer holds the promise of providing lasting therapies and even cures for diseases that were previously untreatable or for which only temporary or suboptimal treatments were available. For some time, clinical gene therapy was characterized by some impressive but rare examples of successes and also several setbacks. However, effective and long-lasting treatments are now being reported from gene therapy trials at an increasing pace. Positive outcomes have been documented for a wide range of genetic diseases (including hematological, immunological, ocular, and neurodegenerativ

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… Nonetheless, successful gene therapies have now been reported for various genetic diseases of the CNS such as adrenoleukodystrophy (ALD), metachromatic leukodystrophy, and aromatic L-amino acid decarboxylase (AADC) deficiency. … Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326: 818–823. Cartier, N, Hacein-Bey-Abina, S, Bartholomae, CC, Bougnères, P, Schmidt, M, Kalle, CV et al. (2012). Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. …

Hyperbaric oxygen therapy in the treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), characterized by inflammation and bleeding of the bladder. Hyperbaric oxygen therapy (HBOT) has been shown to be effective in the treatment of radiation-induced HC. However, the optimal treatment for HC after allogeneic HSCT has not yet been established. Furthermore, limited research has been conducted on the use of HBOT in this setting. This study aimed to evaluate the effectiveness and safety of HBOT in patients with late-onset HC after allogeneic HSCT. METHODS:

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… lymphoma Myeloproliferative neoplasms Acute leukemia of ambiguous lineage Multiple myeloma 55 (90.2%) 17 (27.9%) 13 (21.3%) 7 (11.5%) 6 (7.7%) 5 (8.2%) 3 (4.9%) 2 (3.3%) 1 (1.6%) 1 (1.6%) Non-malignant Hematological Pathology Aplastic anemia Fanconi anemia Paroxysmal nocturnal hemoglobinuria X-linked adrenoleukodystrophy … lymphoma Myeloproliferative neoplasms Acute leukemia of ambiguous lineage Multiple myeloma | 55 (90.2%) 17 (27.9%) 13 (21.3%) 7 (11.5%) 6 (7.7%) 5 (8.2%) 3 (4.9%) 2 (3.3%) 1 (1.6%) 1 (1.6%) Non-malignant Hematological Pathology Aplastic anemia Fanconi anemia Paroxysmal nocturnal hemoglobinuria X-linked adrenoleukodystrophy …

Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies.

The paradigm of pediatric drug development has been evolving in a "carrot-and-stick"-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the United States and the European Pediatric Formulation Initiative have recommended applying nanotechnology-based delivery systems to tackle some of these challenges, particularly applying inorganic, polymeric, and lipid-based nanoparticles. Connected with these, adv

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… adrenoleukodystrophy with no available sibling hematopoietic stem cell donor. | FDA No longer authorized by EMA Vyjuvek | Herpes-simplex virus type 1 vector for delivery of COL7A1 gene | To treat wounds in patients with 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) … Similar clinical benefits were observed in patients with Wiskott–Aldrich syndrome [ 230 , 231 ], X-linked adrenoleukodystrophy, metachromatic leukodystrophy [ 232 , 233 ], or transfusion dependent β-thalassemia [ 234 , 235 , 236 ] treated with lentiviral (LV) HSC therapy. …

GroβT rapidly and reliably mobilizes primitive hematopoietic stem and progenitor cells in nonhuman primates.

Autologous hematopoietic stem cell (HSC) gene therapy has gone through remarkable advancements in recent years, especially for the treatment of sickle cell disease (SCD). However, the collection of HSCs from SCD patients requires unique considerations, as granulocyte colony-stimulating factor (G-CSF)-mediated mobilization is contraindicated, and plerixafor-only mobilization is highly variable. Consequently, alternative mobilization regimens that are safe for SCD patients and generate better cell yields are desirable for SCD HSC gene therapy. Here, we evaluated a combination of plerixafor (AMD3

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… Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818–823. doi: 10.1126/science.1171242. 2. Cartier N., Hacein-Bey-Abina S., Bartholomae C.C., Bougnères P., Schmidt M., Kalle C.V., Fischer A., Cavazzana-Calvo M., Aubourg P. … Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. Methods Enzymol. 2012;507:187–198. doi: 10.1016/B978-0-12-386509-0.00010-7. 3. Li Y., Qiu X., Lei Y., Zhou R. …

Повышенный индекс Каппы в отсутствии Cerebrospinal Fluid IgG Oligoclonal Bands: вклад Intrathecal IgM и IgA Smil.

Индекс " каппа " представляет собой прочно установившийся маркер внутритехального синтеза (ИС) иммуноглобулина (Ig). Обычно используемый для диагностических целей, IgG IS, который может быть оценен количественно (специальные формулы) или качественно (олигоклонные полосы, OCBs), может оказаться неудачным в обнаружении юморальной иммунной реакции в центральной нервной системе (КНС). Основная цель этого исследования состояла в том, чтобы оценить индекс каппы с точки зрения его способности обнаруживать наличие юморального иммунитета CNS и ассоциировать его с отдельной группой расстройств

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… IgA synthesis, on the other hand, prevailed in neurotuberculosis, brain abscess, and adrenoleukodystrophy. Overall, an isolated IS of IgM or IgA was found in 33 and 14% of cases, respectively [ 10 ]. …

Интратективный иммуноглобулин А Обобщение в множестве склероза: от биологических аспектов к клинической значимости.

Интратекальский иммуноглобулин А (IgA) синтез в множестве склерозов (MS) давно не получал достаточного внимания, несмотря на потенциальное значение патогенеза и прогноза заболеваний. Наличие доброкачественных плазменных клеток IgA в повреждениях MS и вдоль поврежденных аксонов свидетельствует о роли в патогенезе болезней. Имеющиеся клинические данные о потенциальной позитивной или негативной прогнозируемой роли являются скудными и неточными. Вместе с тем последние наблюдения свидетельствуют о переходе от кишечника к центральной нервной системе (КНС) в экспериментальные аутоиммунные энцефалитны

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… Accordingly, a dominant intrathecal IgA synthesis is diagnostically informative in neurotuberculosis [ 51 ], brain abscesses, or adrenoleukodystrophy [ 52 ]. …