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1.
Orphanet J Rare Dis ; 19(1): 110, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38462612

RESUMO

BACKGROUND: Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. RESULTS: Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3-17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers' qualitative descriptions of trial experiences suggested improvements in children's verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. CONCLUSIONS: This study revealed caregiver-reported improvements in children's MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.


Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Criança , Pré-Escolar , Humanos , Administração Intravenosa , Cuidadores , Terapia de Reposição de Enzimas , Iduronato Sulfatase/uso terapêutico , Mucopolissacaridose II/tratamento farmacológico , Adolescente
2.
Orphanet J Rare Dis ; 19(1): 104, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38454486

RESUMO

BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.


Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Masculino , Criança , Humanos , Mucopolissacaridose II/tratamento farmacológico , Cuidadores/psicologia , Qualidade de Vida , Japão , Iduronato Sulfatase/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Doenças Raras/tratamento farmacológico
3.
Orphanet J Rare Dis ; 19(1): 109, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459585

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. METHODS: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. RESULTS: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. CONCLUSIONS: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. REGISTRATION: NCT02306720; EUPAS13514.


Assuntos
Dor Crônica , Hipofosfatasia , Imunoglobulina G , Proteínas Recombinantes de Fusão , Adulto , Humanos , Fosfatase Alcalina/uso terapêutico , Hipofosfatasia/tratamento farmacológico , Qualidade de Vida , Estudos Prospectivos , Sistema de Registros , Terapia de Reposição de Enzimas/métodos
4.
J Inherit Metab Dis ; 47(2): 355-365, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38467596

RESUMO

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.


Assuntos
Mucopolissacaridose I , Humanos , Mucopolissacaridose I/tratamento farmacológico , Poliéster Sulfúrico de Pentosana/uso terapêutico , Poliéster Sulfúrico de Pentosana/farmacologia , Cartilagem/metabolismo , Biomarcadores , Dor/tratamento farmacológico , Dor/etiologia , Terapia de Reposição de Enzimas
5.
Nutr Clin Pract ; 39 Suppl 1: S46-S56, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429964

RESUMO

Exocrine pancreatic insufficiency (EPI) is common in pancreatic ductal adenocarcinoma (PDAC) and may lead to significant nutrition compromise. In the setting of cancer cachexia and gastrointestinal toxicities of cancer treatments, untreated (or undertreated) EPI exacerbates weight loss, sarcopenia, micronutrient deficiencies, and malnutrition. Together, these complications contribute to poor tolerance of oncologic therapies and negatively impact survival. Treatment of EPI in PDAC involves the addition of pancreatic enzyme replacement therapy, with titration to improve gastrointestinal symptoms. Medical nutrition therapies may also be applicable and may include fat-soluble vitamin replacement, medium-chain triglycerides, and, in some cases, enteral nutrition. Optimizing nutrition status is an important adjunct treatment approach to improve quality of life and may also improve overall survival.


Assuntos
Insuficiência Pancreática Exócrina , Gastroenteropatias , Desnutrição , Neoplasias Pancreáticas , Humanos , Qualidade de Vida , Pâncreas , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/terapia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/terapia , Desnutrição/etiologia , Nutrição Enteral/efeitos adversos , Terapia de Reposição de Enzimas
6.
Nutr Clin Pract ; 39 Suppl 1: S35-S45, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429966

RESUMO

Surgical resection is the mainstay of treatment for patients with tumors of the pancreas. There are a number of well-recognized complications that account for the significant morbidity associated with the operation, including exocrine pancreatic insufficiency (EPI). Patients with pancreatic cancer commonly have evidence of EPI prior to surgery, and this is exacerbated by an operation, the extent of the insult being dependent on the indication for surgery and the operation performed. There are accumulating data to demonstrate that treatment of EPI with pancreatic enzyme replacement (PERT) enhances clinical outcomes after surgery by reducing critical complications; this in turn may enhance oncological outcomes. Data would indicate that quality of life (QoL) is also improved after surgery when enzymes are prescribed. To date, many surgeons and clinicians have not appreciated the need for PERT or the benefits it may bring to their patients; therefore, education of clinicians remains a significant opportunity. In turn, patient education about consumption of the correct dose of enzymes at the appropriate time is key to an optimal outcome. In addition, because of the complex nature of the regulation of pancreatic exocrine function, there is evidence to support the presence of EPI following operations performed on other gastrointestinal (GI) organs, including the esophagus, stomach, and small intestine. The aim of this review is to document the existing published evidence in relation to EPI and its treatment with PERT following GI surgery.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Insuficiência Pancreática Exócrina , Humanos , Qualidade de Vida , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Pancreatectomia/efeitos adversos , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/etiologia
7.
Orphanet J Rare Dis ; 19(1): 38, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308295

RESUMO

BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.


Assuntos
Doença de Fabry , Isoenzimas , alfa-Galactosidase , Humanos , alfa-Galactosidase/uso terapêutico , Qualidade de Vida , Formação de Anticorpos , Incidência , Resultado do Tratamento , Anticorpos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Itália
8.
Orphanet J Rare Dis ; 19(1): 36, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38303068

RESUMO

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is an ultra-rare autosomal recessive lysosomal storage disorder characterized by intracellular lipid accumulation resulting from reduced function of acid sphingomyelinase. Olipudase alfa, an enzyme replacement therapy, was recently approved in several countries for the treatment of the non-neurologic manifestations of ASMD. Studies demonstrate improvement in organomegaly, pulmonary function and lipid profiles with olipudase alfa, yet little is known about its impact on quality of life (QoL) for patients and caregivers. The purpose of this study is to better understand the real-life impact of ASMD on patients and caregivers and assess how olipudase alfa impacts QoL for pediatric patients and their caregivers. METHODS: Caregivers of pediatric patients (≤ 18 years of age) with a confirmed diagnosis of ASMD that received olipudase alfa for at least 12 months were recruited in early 2022 through national patient organizations to participate in a global online questionnaire followed by semi-structured interviews. Ten caregivers of patients with ASMD who utilized olipudase alfa as an experimental therapy for pediatric patients participated in the study. Quantitative analysis of the results was undertaken, and qualitative data was analyzed using an inductive thematic approach. RESULTS: Ten eligible participants completed questionnaires, and 8 of the 10 went on to participate in structured interviews. Symptom burden of ASMD and impact on symptomatology and quality of life after olipudase alfa use are reported here. Five themes emerged from analysis: (1) ASMD is a systemic disease with a wide array of manifestations that significantly impact QoL; (2) Olipudase alfa was associated with improvements in all non-neurologic manifestations of ASMD; (3) Participants perceived the risk associated with olipudase alfa to be low and the benefits to greatly outweigh any risk or burden; (4) Participants reported an unmet need to treat the neurologic manifestations of the disease despite the benefits of olipudase alfa in the management of non-neurological symptoms; (5) Participants felt all patients with ASMD need access to olipudase alfa based on the life-changing experience they perceived. CONCLUSIONS: These findings highlight the sustained positive impact olipudase alfa had in many domains that are deemed important to patients and families living with ASMD and outline the extensive unmet need for patients and families living with ASMD.


Assuntos
Terapia de Reposição de Enzimas , Doenças de Niemann-Pick , Proteínas Recombinantes , Esfingomielina Fosfodiesterase , Criança , Humanos , Lactente , Terapia de Reposição de Enzimas/métodos , Doenças de Niemann-Pick/terapia , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/uso terapêutico
9.
BMC Nephrol ; 25(1): 61, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383316

RESUMO

Fabry disease (FD) is an uncommon, X-linked, lysosomal storage disease that causes defects in the glycosphingolipid metabolic pathway due to deficient or absent lysosomal α-galactosidase (α-Gal A) activity. This leads to the accumulation of globotriaosylceramide (GL-3) within lysosomes in a wide range of cells, including endothelial, cardiac, renal, and corneal cells, and consequently, the progressive appearance of clinical symptoms in target organs. Enzyme replacement therapy (ERT), which involves the exogenous supplementation of α-Gal A enzyme and has been successfully administered for treating FD.Here, we report a case of a 37-year-old male with complaints of recurrent proteinuria and ventricular septal thickening. A renal biopsy revealed vacuolization and foamy changes in podocytes, and the presence of myelin-like bodies and zebra bodies. The white blood cell α-Gal A activity was very low, while the Lyso-GL-3 level was high. Additionally, genetic analysis revealed a gene variant c.902G > A p. Arg301Gln. The patient was diagnosed with FD, and subsequently received intravenous ERT with a dose of Agalsidase α (0.2 mg/kg, 17.5 mg every 2 weeks). Currently, the values of proteinuria and ventricular septum thickness remain stable during the 6-month follow-up. Initiating ERT at an early age can effectively decrease the deposition of GL-3, attenuate the progressive clinical manifestations of FD, and provide greater long-term benefits.


Assuntos
Doença de Fabry , Masculino , Humanos , Adulto , Doença de Fabry/complicações , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Terapia de Reposição de Enzimas , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêutico , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Rim/patologia , Ventrículos do Coração/patologia
10.
Int J Mol Sci ; 25(4)2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38397051

RESUMO

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood-brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II-thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.


Assuntos
Mucopolissacaridose I , Feminino , Camundongos , Animais , Mucopolissacaridose I/tratamento farmacológico , Iduronidase/uso terapêutico , Genisteína/farmacologia , Genisteína/uso terapêutico , Encéfalo , Barreira Hematoencefálica , Glicosaminoglicanos/uso terapêutico , Trombina/uso terapêutico , Modelos Animais de Doenças , Terapia de Reposição de Enzimas/métodos
11.
Eur J Med Genet ; 68: 104915, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38325645

RESUMO

Hypophosphatasia (HPP) is a rare disorder, resulting from loss-of-function variants of the ALPL gene encoding non-tissue specific alkaline phosphatase (TNSALP). Presentation varies largely, with increased severity usually occurring with earlier disease onset. Here we describe the clinical improvement of a 57-year-old woman with childhood onset HPP, after initiating treatment with asfotase alfa (Strensiq®). This was started because of the rapid and progressive radiological deterioration of bone structure after placement of nails in both upper legs for spontaneous atypical femur fracture (AFF) - like fractures. Initiation of treatment, not only resulted in stabilization of bone structure on X-rays, but within a few weeks there was a dramatic reduction of burning pain sensations in the lower legs, attributed in retrospect to neuropathic pain, and also almost complete disappearance of headaches. Additionally, unhealed metatarsal fractures finally healed after almost 10 years. Drug efficacy was further evaluated through -quality of life questionnaires and multiple tests conducted by the physiotherapist, and showed clear improvements. Within 3 months after starting asfotase alfa, the patient was able to carry out her daily tasks indoors without relying on a walker and even started electric bike rides for 20 km/day. In conclusion, treatment with asfotase alfa, halted rapid radiological bone deterioration after bilateral intramedullary femoral pen placement and strongly increased quality of life, marked by rapid disappearance of neuropathic pain, reduction in headaches and musculoskeletal pains, and enhanced muscle strength and mobility. The quick and almost complete disappearance of neuropathic pain and headache suggests a relation with disturbed levels of metabolites in HPP.


Assuntos
Hipofosfatasia , Imunoglobulina G , Neuralgia , Proteínas Recombinantes de Fusão , Adulto , Feminino , Humanos , Criança , Pessoa de Meia-Idade , Fosfatase Alcalina/uso terapêutico , Hipofosfatasia/complicações , Hipofosfatasia/tratamento farmacológico , Qualidade de Vida , Terapia de Reposição de Enzimas/métodos , Neuralgia/tratamento farmacológico , Cefaleia/tratamento farmacológico
12.
N Engl J Med ; 390(7): 623-629, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354141

RESUMO

Wolman's disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman's disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood.


Assuntos
Gorduras na Dieta , Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos , Rituximab , Doença de Wolman , Humanos , Lactente , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Quimerismo , Gorduras na Dieta/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Transplante Homólogo , Doença de Wolman/dietoterapia , Doença de Wolman/tratamento farmacológico , Doença de Wolman/imunologia , Doença de Wolman/terapia
13.
Front Immunol ; 15: 1307558, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38304433

RESUMO

Defective α-galactosidase A (AGAL/GLA) due to missense or nonsense mutations in the GLA gene results in accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and its deacylated derivate globotriaosylsphingosine (lyso-Gb3) in cells and body fluids. The aberrant glycosphingolipid metabolism leads to a progressive lysosomal storage disorder, i. e. Fabry disease (FD), characterized by chronic inflammation leading to multiorgan damage. Enzyme replacement therapy (ERT) with agalsidase-alfa or -beta is one of the main treatment options facilitating cellular Gb3 clearance. Proteome studies have shown changes in complement proteins during ERT. However, the direct activation of the complement system during FD has not been explored. Here, we demonstrate strong activation of the complement system in 17 classical male FD patients with either missense or nonsense mutations before and after ERT as evidenced by high C3a and C5a serum levels. In contrast to the strong reduction of lyso-Gb3 under ERT, C3a and C5a markedly increased in FD patients with nonsense mutations, most of whom developed anti-drug antibodies (ADA), whereas FD patients with missense mutations, which were ADA-negative, showed heterogenous C3a and C5a serum levels under treatment. In addition to the complement activation, we found increased IL-6, IL-10 and TGF-ß1 serum levels in FD patients. This increase was most prominent in patients with missense mutations under ERT, most of whom developed mild nephropathy with decreased estimated glomerular filtration rate. Together, our findings demonstrate strong complement activation in FD independent of ERT therapy, especially in males with nonsense mutations and the development of ADAs. In addition, our data suggest kidney cell-associated production of cytokines, which have a strong potential to drive renal damage. Thus, chronic inflammation as a driver of organ damage in FD seems to proceed despite ERT and may prove useful as a target to cope with progressive organ damage.


Assuntos
Doença de Fabry , Humanos , Masculino , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Doença de Fabry/metabolismo , Terapia de Reposição de Enzimas , Códon sem Sentido , Rim/metabolismo , Anticorpos/genética , Ativação do Complemento
14.
Sci Transl Med ; 16(730): eadf1691, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38232139

RESUMO

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Camundongos , Animais , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Glicogênio Sintase/metabolismo , Glicogênio Sintase/farmacologia , Camundongos Knockout , Glicogênio/metabolismo , Músculo Esquelético/metabolismo , Terapia de Reposição de Enzimas/métodos
15.
J Patient Rep Outcomes ; 8(1): 13, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38294575

RESUMO

BACKGROUND: The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT). METHODS: In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers' maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients' age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods. RESULTS: 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively. CONCLUSIONS: PROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www. CLINICALTRIALS: gov/search?term=NCT03729362 .


Assuntos
Doença de Depósito de Glicogênio Tipo II , Adulto , Humanos , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Índice de Massa Corporal , Correlação de Dados , Terapia de Reposição de Enzimas , Medidas de Resultados Relatados pelo Paciente
16.
Mol Genet Metab ; 141(2): 108119, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38184429

RESUMO

INTRODUCTION: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. METHOD: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. RESULTS: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DISCUSSION: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Criança , Masculino , Feminino , Humanos , Adolescente , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Convulsões/diagnóstico por imagem , Convulsões/etiologia , Fatores de Risco , Terapia de Reposição de Enzimas/métodos , alfa-Glucosidases/uso terapêutico
18.
Orphanet J Rare Dis ; 19(1): 14, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216959

RESUMO

BACKGROUND: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. METHODS: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded. RESULTS: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018). CONCLUSION: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Produção de Droga sem Interesse Comercial , Doenças Raras/tratamento farmacológico , Resultado do Tratamento , Terapia de Reposição de Enzimas/métodos , alfa-Glucosidases/uso terapêutico
19.
Curr Opin Ophthalmol ; 35(3): 232-237, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38170785

RESUMO

PURPOSE OF REVIEW: This paper provides an update on intravitreal (IVT) enzyme replacement therapy (ERT) in metabolic retinal diseases; particularly neuronal ceroid lipofuscinosis type 2 (CLN2) also known as Batten disease. RECENT FINDINGS: ERT is being explored in CLN2 related Batten disease, a fatal neurodegenerative condition associated with retinopathy and blindness that is caused by the deficiency of lysosomal enzyme TPP1. Cerliponase alfa, a recombinant human tripeptidyl-peptidase1 (rhTPP1) administered by intraventricular infusions has been demonstrated to slow the rate of neurodegenerative decline but not retinopathy. A preclinical study of IVT rhTPP1 in a CLN2 canine model demonstrated efficacy in preserving retinal function and retinal morphology shown on histology. More recently, intravitreal (IVT) administration of rhTPP1 was reported in a first-in-human compassionate use study. Patients received 12-18 months of 8-weekly IVT ERT (0.2 mg rhTPP-1 in 0.05 ml) in one eye. No significant ocular adverse reactions were reported. Treatment decreased the rate of retinal thinning but modestly. SUMMARY: The evidence suggests that IVT ERT with rhTPP1 may be a safe and effective treatment for CLN2 retinopathy. However, the optimal dosage and frequency to achieve the best possible outcomes requires further investigation as does patient selection.


Assuntos
Lipofuscinoses Ceroides Neuronais , Degeneração Retiniana , Humanos , Animais , Cães , Tripeptidil-Peptidase 1 , Aminopeptidases/genética , Aminopeptidases/efeitos adversos , Serina Proteases/uso terapêutico , Serina Proteases/efeitos adversos , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/complicações , Degeneração Retiniana/tratamento farmacológico , Terapia de Reposição de Enzimas/efeitos adversos
20.
Expert Rev Neurother ; 24(3): 259-266, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38261315

RESUMO

INTRODUCTION: Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time. AREAS COVERED: The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components. EXPERT OPINION: There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Adulto , Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Terapia de Reposição de Enzimas/efeitos adversos , Autofagia , Ensaios Clínicos Controlados Aleatórios como Assunto
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