Enzyme Replacement Research Articles

Advances in Diagnosis and Treatment of Fabry Disease: A Review of Clinical Manifestations and Therapeutic Interventions

At present, early diagnosis of many orphan diseases is difficult due to their rare occurrence and insufficient knowledge of them. This article presents a review of the literature and our study of Fabry disease (FD), a rare genetic multisystem disease which belongs to the group of lysosomal storage diseases. This disease is based on a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to the progressive accumulation of glycolipid Gb3 in lysosomes in almost all cells of the body, causing extensive organ damage and an increase in plasma levels of globotriaosylsphingosine (lyso-Gb3 product of degradation of accumulated Gb3. Objective: The aim is to provide a comprehensive overview of modern knowledge and current research in the field of pathophysiology, diagnosis and treatment of heart damage in FD, to evaluate the characteristics of diagnosed patients living on the territory of the Moscow region, and to develop and propose for spreading an algorithm for the early detection of this pathology. Methods: A retrospective analysis of the medical records of 12 patients with an estab-lished diagnosis of Fabry disease was carried out. Data from 12 patients with FD, undergoing enzyme replacement therapy of varying durations were analyzed. All patients had left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy, with 9 having LVH diagnosed during a diagnosis. 7 patients get a cardioprotective therapy. All patients underwent molecular genetic testing. In 3 cases there was fa-tal case. Results: The data were analyzed and molecular genetic markers of FD were detected for the purpose of selective screening for FD in the study sample. Conclusion: An algorithm for the early diagnosis of FD has been developed and presented for distribution among general practitioners and cardiologists.

Pancreatitis in cystic fibrosis: Presentation, medical and surgical management, and the impact of modulator therapies.

Patients with Cystic Fibrosis (CF) are at increased risk of acute (AP) and chronic (CP) pancreatitis, and their complications. The extent of remaining healthy pancreatic parenchyma determines the risk of developing future episodes of pancreatitis, as well as pancreatic exocrine or endocrine insufficiency. Pancreatitis may be the presenting symptom of CF, and genetic testing is especially important in pediatrics. AP and recurrent AP are managed with intravenous fluid hydration and pain control, in addition to early refeeding and treatment of complications. With the use of modulator therapy in CF, pancreatic function may be restored to some extent. CP related pain is managed with analgesics and neuromodulators, with surgery if indicated in specific situations including TPIAT as a possible type of surgical intervention. Long-term sequelae of CP in patients with CF include exocrine pancreatic insufficiency treated with pancreatic enzyme replacement therapy, fat-soluble vitamin deficiencies and associated metabolic complications such as bone disease/osteoporosis, pancreatogenic diabetes, and less commonly, pancreatic cancer. We review the presentation and etiologies of pancreatitis in CF patients as well as the management of AP and CP primarily in children.

Association of in-line digestive enzyme cartridge with enteral feeds on improvement in anthropometrics among pediatric patients with cystic fibrosis.

Approximately 85% of patients with cystic fibrosis (CF) have exocrine pancreatic insufficiency (EPI) with 10% requiring supplemental nighttime enteral tube feedings. Administration of pancreatic enzyme replacement therapy (PERT) with nighttime feedings is fraught with challenges. RELiZORB (Alcresta Therapeutics, Inc), an in-line lipase cartridge, delivers PERT continuously with enteral feedings. Outcomes related to the use of this in-line lipase cartridge are lesser known. This project evaluated anthropometrics related to in-line lipase cartridge use among pediatric patients with CF already receiving oral PERT therapy prior to nighttime enteral feedings. Retrospective chart review was performed on 29 patients with CF and EPI receiving supplemental tube feedings and utilizing in-line lipase cartridge for a continuous 12 month period between 2015 and 2019. Anthropometrics were evaluated 12 months before and after initiation of in-line lipase cartridge. Compared with mean height z score at 6-months pre-in-line lipase cartridge, mean height z score at 6-months post-in-line-lipase cartridge (adjusted mean difference [AMD] = 0.2540; 95% CI = [0.0487, 0.4592]; P = 0.0153) and mean height z score at 12-months post-in-line lipase cartridge (AMD = 0.2684; 95% CI = [0.0203, 0.5166]; P = 0.0340) were significantly higher. Mean weight z score at 12-months post-in-line-lipase-cartridge neared statistical significance compared with 6-months pre-in-line lipase cartridge (AMD = 0.2816; 95% CI = [-0.0003, 0.5634]; P = 0.0502) when excluding seven patients with advanced lung disease (forced expiratory volume in the first second of expiration of 40%). Weight-for-length or body mass index did not significantly differ compared with pre-in-line lipase cartridge. Use of in-line lipase cartridge with enteral feeds improved anthropometrics, especially height, in pediatric patients with CF.

Emerging trends in disturbed function of the pancreas and dyspepsia: an Indian perspective

Disturbed function of the pancreas, especially exocrine pancreatic insufficiency (EPI) results in inadequate synthesis or delivery of the pancreatic enzyme leading to maldigestion. Due to the lack of specific symptoms and overlapping manifestations of EPI, it often goes undiagnosed and untreated. Dyspepsia is another common condition characterized by upper gastrointestinal symptoms caused by a heterogeneous group of disorders. This consensus aims at providing a comprehensive overview of the diagnosis and management of disturbed function of the pancreas and dyspepsia. A total of 95 gastroenterologists participated in expert group meetings organized via virtual focus group discussions. Recent evidence elaborating various aspects like diagnosis and management of EPI and dyspepsia, including the use of pancreatic enzyme replacement therapy (PERT) and issues with compliance were discussed. The experts emphasized that clinical symptoms of maldigestion should not be ignored, and physicians should not wait to diagnose EPI until steatorrhea occurs. Fecal elastase (FE) test and imaging should be performed to confirm diagnosis. If EPI is diagnosed or the patient experiences weight loss or steatorrhea, PERT should be initiated while ensuring compliance. Reducing pill burden, active education, monitoring, and support from healthcare programs may help ensure compliance. EPI is also a cause of dyspepsia. Further, consuming lipid-rich foods worsens symptoms of dyspepsia. First-line treatment includes dietary changes and lifestyle modifications. Digestive enzyme supplements play a significant role in alleviating symptoms of indigestion. Routine enzyme supplementation is beneficial in managing dyspepsia caused by EPI, such as, in patients with EPI due to pancreatitis or diabetes.

Advancements in Viral Gene Therapy for Gaucher Disease.

Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the GBA1 gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood-brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease.

Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I.

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.

Caregiver experiences and observations of intrathecal idursulfase-IT treatment in a phase 2/3 trial in pediatric patients with neuronopathic mucopolysaccharidosis II

BackgroundApproximately 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.ResultsOverall, 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.ConclusionsThis 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.

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective.

Rare diseases are particular pathological conditions affecting a limited number of people and few drugs are known to be effective as therapeutic treatment. Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, belongs to this class of disorders, and it is considered the most common among the Lysosomal Storage Diseases. The two main therapeutic approaches are the Enzyme Replacement Therapy (ERT) and the Substrate Reduction Therapy (SRT). ERT, consisting in replacing the defective enzyme by administering a recombinant enzyme, is effective in alleviating the visceral symptoms, hallmarks of the most common subtype of the disease whereas it has no effects when symptoms involve CNS, since the recombinant protein is unable to significantly cross the Blood Brain Barrier. The SRT strategy involves inhibiting glucosylceramide synthase (GCS), the enzyme responsible for the production of the associated storage molecule. The rational design of new inhibitors of GCS has been hampered by the lack of either the crystal structure of the enzyme or an in-silico model of the active site which could provide important information regarding the interactions of potential inhibitors with the target, but, despite this, interesting results have been obtained and are herein reviewed.

Congenital sucrase–isomaltase deficiency in Türkiye; a single center experience

Background Congenital sucrase–isomaltase deficiency (CSID) is a rare inherited carbohydrate malabsorption disorder caused by sucrase–isomaltase (SI) gene variants. In CSID, an autosomal recessively inherited disease, symptoms can also be seen in individuals with heterozygous mutations. Methods The variant spectrum was evaluated retrospectively in individuals who presented with chronic diarrhea between 2014 and 2022 and had undergone genetic testing of the SI gene considering CSID due to diet-related complaints. Results Ten patients with chronic diarrhea were genetically evaluated with SI gene sequencing. In patients diagnosed with CSID and whose symptoms improved with enzyme replacement therapy, the genetic mutation zygosity was found to be heterozygous at a rate of 90%. In 10% of the patients, the mutation was homozygous. Limiting consuming sucrose and isomaltose foods reduced the patients’ complaints, but the symptoms did not disappear completely. With the initiation of sacrosidase enzyme replacement therapy, the patient’s complaints completely disappeared. Conclusion In CSID, defined as an autosomal recessive disease, clinical symptoms can also be seen in heterozygous cases previously described as carriers, and these patients also benefit from sacrosidase enzyme replacement therapy. In light of these findings, the autosomal recessive definition of CSID does not fully characterize the disease. What is Known: CSID is a rare inherited carbohydrate malabsorption disorder caused by sucrase–isomaltase gene variants. In congenital sucrase–isomaltase deficiency, an autosomal recessively inherited disorder, symptoms can also be seen in individuals with heterozygous mutations. What is new: Severe disease symptoms can also be seen in heterozygous cases, which were thought to be carriers because the disease was previously described as autosomal recessive. Sacrosidase enzyme replacement therapy also eliminates the disease symptoms in patients with heterozygous CSID mutations. This is the second study on sucrase–isomaltase enzyme deficiency pediatric groups in Türkiye and Europe.

Effectiveness of asfotase alfa for treatment of adults with hypophosphatasia: results from a global registry

BackgroundHypophosphatasia (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.MethodsThe 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.ResultsA 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.ConclusionsAdults 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.

Experience of correction of enzyme therapy in children with cystic fibrosis using computer systems and means of network communication

Justification. In recent years, great progress in the treatment of cystic fibrosis has been associated with the use of pathogenetic therapy (since 2012 - in world practice, since 2020 in the Russian Federation). Against the background of the use of which the nutritional status, the functional state of the lungs improves, but there is no complete restoration of the impaired functions of the organs, in particular, the external secretory function of the pancreas is restored only in young children with the timely appointment of targeted therapy The purpose of the study: to increase the effectiveness of correction of enzyme replacement therapy by an individualized approach. Methods. 140 children (boys - 81, girls - 59) with MV aged from 1 year to 18 years (average age 12.9±4.8 years) were examined. The study was conducted in 2022 in the Department of Cystic Fibrosis Scientific and «Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Region» (clinical base of the scientific and clinical Department of Cystic fibrosis Research Center for Medical Genetic). Inclusion criteria - diagnosis of cystic fibrosis, chronic pancreatic insufficiency, severe. Exclusion criteria - short bowel syndrome, exacerbation of the disease. The doses of pancreatin per day were evaluated using the calculation method: units/g of fat in food and intestinal syndrome before and after correction using an algorithm of an individualized approach to calculating enzyme therapy. The observation period is 3 months Design: single-center, prospective, comparative Results. The study showed that the majority of 82 patients (59%) in the general group received less than 2000 U/g of fat, which is less than the reference values (2000-4000 U/g). The median daily dose was 1500 U / g of fat, which can be attributed to the peculiarities of dosing and the need for pancreatin in the Russian pediatric population of patients with cystic fibrosis. The results are consistent with the data of recent studies indicating an acceptable dosage range of pancreatin 1000-4000 units / g of fat in food. In the course of the study, an algorithm for individualized correction of enzyme replacement therapy was developed and the effectiveness of this approach was shown. Conclusion. When calculating pancreatin for the fat content in food, the dose was below the recommended values of 2000-4000 units / g and amounted to 1500 units / g, which indicated that it did not meet the needs of children in enzymes and required individual correction. This served as the basis for the development of an algorithm for individualized correction of enzyme replacement therapy. The effectiveness of this approach using computer technology (inpatient program for doctors and mobile version for patients), in the form of reduction / relief of intestinal syndrome, is shown. To increase compliance and to train parents to control diet and enzyme replacement therapy, it is advisable to use computer programs and mobile applications to calculate the diet and dosage of pancreatin for each meal.

Analysis of caregiver perspectives on patients with mucopolysaccharidosis II treated with pabinafusp alfa: results of qualitative interviews in Japan

BackgroundMucopolysaccharidosis 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.MethodsSemi-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.ResultsSeven 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.ConclusionCaregivers’ 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.

Rational Prescribing of Pancreatic Enzymes for Patients with Pancreatic Cancer.

Most patients with pancreatic cancer at some point present with symptoms related to exocrine pancreatic insufficiency (EPI). These include diarrhea, abdominal bloating, indigestion, steatorrhea, weight loss, and anorexia. Even though up to 80% of pancreatic cancer patients eventually present with symptoms related to exocrine pancreatic insufficiency, only 21% are prescribed pancreatic enzyme replacement therapy (PERT). Its effectiveness is also highly dependent on its proper timing of administration, and patients must be thoroughly educated about this. The impact of symptoms of EPI can lead to poorer overall well-being. Pharmacists play a crucial role in properly educating patients on the correct use of pancreatic enzyme replacement therapy. PERT is a key strategy in managing the symptoms of EPI and can improve quality of life, which is a central focus in palliative care. This treatment is profoundly underutilized in the palliative care of these patients. The objective of this review is to discuss the pharmacology, pharmacokinetics, side effects, available evidence of the effectiveness of pancreatic enzyme use for patients with pancreatic cancer, and challenges, along with proposed solutions regarding its use.

Gaucher Disease or Acid Sphingomyelinase Deficiency? The Importance of Differential Diagnosis.

Background: Gaucher disease is a lysosomal storage disorder caused by functional glucocerebrosidase enzyme deficiency. Hepatosplenomegaly and hematological complications are found in both Gaucher disease and Acid Sphingomyelinase Deficiency, which is caused by acid sphingomyelinase dysfunction. The possible overlap in clinical presentation can cause diagnostic errors in differential diagnosis. For this reason, in patients with an initial clinical suspicion of Gaucher disease, we aimed to carry out a parallel screening of acid sphingomyelinase and glucocerebrosidase. Methods: Peripheral blood samples of 627 patients were collected, and enzymatic activity analysis was performed on both glucocerebrosidase and acid sphingomyelinase. The specific gene was studied in samples with null or reduced enzymatic activity. Specific molecular biomarkers helped to achieve the correct diagnosis. Results: In 98.7% of patients, normal values of glucocerebrosidase activity excluded Gaucher disease. In 8 of 627 patients (1.3%), the glucocerebrosidase enzymatic activity assay was below the normal range, so genetic GBA1 analysis confirmed the enzymatic defect. Three patients (0.5%) had normal glucocerebrosidase activity, so they were not affected by Gaucher disease, and showed decreased acid sphingomyelinase activity. SMPD1 gene mutations responsible for Acid Sphingomyelinase Deficiency were found. The levels of specific biomarkers found in these patients further strengthened the genetic data. Conclusions: Our results suggest that in the presence of typical signs and symptoms of Gaucher disease, Acid Sphingomyelinase Deficiency should be considered. For this reason, the presence of hepatosplenomegaly, thrombocytopenia, leukocytopenia, and anemia should alert clinicians to analyze both enzymes by a combined screening. Today, enzyme replacement therapy is available for the treatment of both pathologies; therefore, prompt diagnosis is essential for patients to start accurate treatment and to avoid diagnostic delay.

The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.

Parkinson's disease (PD) is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular etiology of the disease is still unclear. Several cellular pathways have been linked to PD, including the autophagy-lysosome pathway (ALP), α-synuclein (α-syn) aggregation, and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and PD lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid buildup, disrupting lysosomal function and autophagy, thereby triggering α-syn accumulation. Additionally, α-syn aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-syn accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine-adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in PD pathogenesis and discuss promising examples of GCase-based therapeutics such as gene and enzyme replacement therapies, small molecule chaperones, and substrate reduction therapies, among others, as potential therapeutic interventions.

How Precise are Nanomedicines in Overcoming the Blood-Brain Barrier? A Comprehensive Review of the Literature.

New nanotechnology strategies for enhancing drug delivery in brain disorders have recently received increasing attention from drug designers. The treatment of neurological conditions, including brain tumors, stroke, Parkinson's Disease (PD), and Alzheimer's disease (AD), may be greatly influenced by nanotechnology. Numerous studies on neurodegeneration have demonstrated the effective application of nanomaterials in the treatment of brain illnesses. Nanocarriers (NCs) have made it easier to deliver drugs precisely to where they are needed. Thus, the most effective use of nanomaterials is in the treatment of various brain diseases, as this amplifies the overall impact of medication and emphasizes the significance of nanotherapeutics through gene therapy, enzyme replacement therapy, and blood-barrier mechanisms. Recent advances in nanotechnology have led to the development of multifunctional nanotherapeutic agents, a promising treatment for brain disorders. This novel method reduces the side effects and improves treatment outcomes. This review critically assesses efficient nano-based systems in light of obstacles and outstanding achievements. Nanocarriers that transfer medications across the blood-brain barrier and nano-assisted therapies, including nano-immunotherapy, nano-gene therapy, nano enzyme replacement therapy, scaffolds, and 3D to 6D printing, have been widely explored for the treatment of brain disorders. This study aimed to evaluate existing literature regarding the use of nanotechnology in the development of drug delivery systems that can penetrate the blood-brain barrier (BBB) and deliver therapeutic agents to treat various brain disorders.

The Impact of Pabinafusp Alfa on the Disease Burden in Hunter's Syndrome: Patient-Reported Outcomes

AbstractSevere mucopolysaccharidosis type II (MPS-II) patients present with progressive mental impairment and reduced life expectancy. While current available treatment cannot cross the blood–brain barrier, the enzyme replacement therapy with pabinafusp alfa (a recombinant iduronate-2-sulfatase fused to an antihuman transferrin receptor antibody) was designed to penetrate it using transferrin receptor-mediated transcytosis. In this cross-sectional retrospective study, we aimed to report the impact of this new therapy using patient-reported outcomes. Data were collected using standardized questionnaire replied by patients or their caregivers (as proxies). Nine patients received intravenous administration of pabinafusp alfa for at least 104 weeks. All patient showed improvements in behavior (mainly aggressiveness), speech, motor ability, muscle strength, facial expression, breathing, and cognitive skills. Gait improvement was also found in 78% of participants. Caregivers also reported improvements in emotion demonstration as ability to smile, establish eye contact, and give hugs. Collectively, our results indicate a positive impact of pabinafusp alfa on quality of life of individuals with MPS-II and their relatives/caregivers. Future studies are warranted to elucidate the mechanisms underlying these beneficial effects.

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy.

Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF.

Fat malabsorption in pancreatic cancer: Pathophysiology and management.

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.

Exocrine pancreatic insufficiency and pancreatic exocrine replacement therapy in clinical practice.

Exocrine pancreatic insufficiency (EPI) is a complex condition that disrupts normal digestion and absorption. Patients with EPI may suffer from mild to debilitating malabsorption with a constellation of symptoms that can have a significant effect on quality of life and nutrition status. Pancreatic enzyme replacement therapy (PERT) is effective and safe to treat EPI and is the standard of care for this condition. A wide variety and various forms of these products exist, as well as numerous guidelines and recommendations. Obtaining PERT for patients can oftentimes be cost prohibitive. Determining the presence and extent of EPI can be challenging and patient specific, making it difficult for practitioners. This narrative review will explore these issues, as well as several disease states potentially affected by EPI, and review current management strategies.