RNA Therapeutics to Control Fibrinolysis: Review on Applications in Biology and Medicine.

Regulation of fibrinolysis, the process that degrades blood clots, is pivotal in maintaining haemostasis. Dysregulation leads to thrombosis or excessive bleeding. Proteins in the fibrinolysis system include fibrinogen, coagulation factor XIII, plasminogen, tissue plasminogen activator (tPA), urokinase (uPA), α2-antiplasmin, thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1), α2-macroglobulin, and others. While each of these is a potential therapeutic target for diseases, they each lack effective or long-acting inhibitors. Rapid advances in RNA-based technologies are creating powerful tools to control the expression of proteins. RNA agents can be long-acting and tailored to either decrease or increase production of a specific protein. Advances in nucleic acid delivery, such as by lipid nanoparticles, have enabled the delivery of RNA to the liver, where most proteins of coagulation and fibrinolysis are produced. This review will summarize the classes of RNA that induce 1) inhibition of protein synthesis, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs); 2) protein expression including messenger RNA (mRNA) and self-amplifying RNA (saRNA); and 3) gene editing for gene knockdown and precise editing. It will review specific examples of RNA therapies targeting proteins in the coagulation and fibrinolysis systems, and comment on the wide range of opportunities for controlling fibrinolysis for biological applications and future therapeutics using state-of-the-art RNA therapies.

Fabry disease: a rare disorder calling for personalized medicine.

Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon.

Does administration of hydroxychloroquine/amiodarone affect the efficacy of enzyme replacement therapy for Fabry mice?

As a standard therapy for Fabry disease, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal) has been successfully used, and the instructions for this drug state that "it should not be co-administrated with cationic amphiphilic drugs such as hydroxychloroquine (HCQ) and amiodarone (AMI), since these drugs have the potential to inhibit intracellular α-Gal activity". However, there would be cases in which HCQ or AMI is required for patients with Fabry disease, considering their medical efficacy and application. Thus, we examined the impact of HCQ/AMI on recombinant human α-Gal by in vitro, cellular, and animal experiments. The results revealed that HCQ/AMI affected the enzyme activity of α-Gal incorporated into cultured fibroblasts from a Fabry mouse when the cells were cultured in medium containing these drugs and the enzyme, although their direct inhibitory effect on the enzyme is not strong. These lysosomotropic drugs may be trapped and concentrated in lysosomes, followed by inhibition of α-Gal. On the other hand, no reduction of α-Gal activity incorporated into the organs and tissues, or acceleration of glycoshingolipid accumulation was observed in Fabry mice co-administered with HCQ/AMI and the enzyme, compared with in the case of usual ERT. As HCQ/AMI administered are catabolized in the liver, these drugs possibly do not affect ERT for Fabry mice, different from in the case of cultured cells in an environment isolated from the surroundings.

Patient-reported experience with Fabry disease and its management in the real-world setting: results from a double-blind, cross-sectional survey of 280 respondents.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.

Impacts of pancreatic exocrine insufficiency on gut microbiota. / èƒ°è ºå¤–åˆ†æ³ŒåŠŸèƒ½ä¸å ¨å¯¹è‚ é“å¾®ç”Ÿç‰©ç¾¤çš„å½±å“.

Pancreatic exocrine insufficiency (PEI) can be induced by various kinds of diseases, including chronic pancreatitis, acute pancreatitis, and post-pancreatectomy. The main pathogenetic mechanism of PEI involves the decline of trypsin synthesis, disorder of pancreatic fluid flow, and imbalance of secretion feedback. Animal studies have shown that PEI could induce gut bacterial overgrowth and dysbiosis, with the abundance of Lactobacillus and Bifidobacterium increasing the most, which could be partially reversed by pancreatic enzyme replacement therapy. Clinical studies have also confirmed the association between PEI and the dysbiosis of gut microbiota. Pancreatic exocrine secretions and changes in duodenal pH as well as bile salt malabsorption brought about by PEI may affect and shape the abundance and composition of gut microbiota. In turn, the gut microbiota may impact the pancreatic exocrine acinus through potential bidirectional crosstalk. Going forward, more and higher-quality studies are needed that focus on the mechanism underlying the impact of PEI on the gut microbiota.

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data.

The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT's clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.

Long-Term Clinical-Pathologic Results of Enzyme Replacement Therapy in Prehypertrophic Fabry Disease Cardiomyopathy.

BACKGROUND: The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM. METHODS AND RESULTS: Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and ß-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with ß-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation. CONCLUSIONS: ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.

Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis.

Introduction: Pompe disease (PD) is a glycogen disorder caused by the deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for infantile-onset PD (IOPD). Methods: We systematically searched the MEDLINE (via PubMed) and Embase databases for prospective clinical studies evaluating ERT for IOPD on pre-specified outcomes. Meta-analysis was also performed. Results: Of 1,722 articles identified, 16 were included, evaluating 316 patients. Studies were heterogeneous and with very low certainty of evidence for most outcomes. A moderate/high risk of bias was present for most included articles. The following outcomes showed improvements associated with alglucosidase alfa, over natural history of PD/placebo, for a mean follow-up of 48.3 months: left ventricular (LV) mass {mean change 131.3 g/m2 [95% confidence interval (CI) 81.02, 181.59]}, time to start ventilation (TSV) [HR 0.21 (95% CI: 0.12, 0.36)], and survival [HR 0.10 (95% CI: 0.05, 0.19)]. There were no differences between the pre- and post-ERT period for myocardial function and psychomotor development. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Our data suggest that alglucosidase alfa potentially improves LV mass, TSV, and survival in IOPD patients, with no important safety issues. Systematic Review Registration: PROSPERO identifier (CRD42019123700).

Management of patients with phenylketonuria (PKU) under enzyme replacement therapy: An Italian model (expert opinion).

Objective: Phenylketonuria (PKU) is a metabolic disorder necessitating lifelong management to prevent severe neurological impairments. This paper synthesises clinical practices from Italian specialist centres to delineate a unified approach for administering pegvaliase, a novel enzyme replacement therapy for PKU. Methods: Virtual meetings convened in September 2022, gathering a steering committee (SC) of experts from five Italian centres specialising in PKU. The SC reviewed, and discussed clinical practices, and formulated recommendations for pegvaliase treatment. Results: The SC outlined a comprehensive treatment roadmap for PKU management with pegvaliase, emphasising the importance of multidisciplinary care teams, patient selection, pre-treatment evaluation, and education. Recommendations include initial hospital-based pegvaliase administration, regular monitoring of phenylalanine and tyrosine levels, dietary adjustments, and management of adverse events. A consensus was reached on the need for a digital database to manage treatment plans and enhance communication between healthcare professionals and patients. Conclusion: The expert panel's consensus highlights the complexity of PKU management and the necessity for a coordinated, patient-centred approach. The recommendations aim to standardise care across Italian centres and provide a framework for integrating pegvaliase therapy into clinical practice, potentially informing international guidelines. Further research is warranted to evaluate the long-term impact of these practices on patient outcomes and quality of life.

Taliglucerase alfa in the longterm treatment of children and adolescents with type 1 Gaucher disease: the Albanian experience.

Introduction: Enzyme replacement therapy is already recognized as the gold standard of care for patients with Gaucher disease. Taliglucerase alfa is one of the three alternatives recommended for treatment of Gaucher disease in children and adults. Aim: This study aims to evaluate the long-term efficacy and safety of Taliglucerase alfa in children and adolescents with Type 1 Gaucher disease. Patients and methods: Over a six-year period, we monitored the efficacy of continuous treatment in 10 patients by assessing various parameters, including hemoglobin concentration, platelet count, liver and spleen volume, bone mineral density, glucosylsphingosine level, chitotriosidase activity, and growth parameters. Safety was evaluated by immunogenicity and adverse event monitoring. Results: The mean age of patients was 13.4 ± 3.6 years and the treatment duration was 60.24 ± 13.4 months. From baseline to end line the parameters change as follows: hemoglobin concentration improved from 12.7 (±1.3) to 14.6 (±1.5) and platelet count from 180 (±74) to 198 (±79). The spleen volume, was reduced by 46% (p = 0,007). The chitotriosidase activity decreased from 4,019.7 (±3,542.0) nmoles/ml/hr to 2,039.5 (±1,372.2) nmoles/ml/hr (46% reduction). Glucoylsphingosine level dropped from 119.2 (±70.4) ng/ml to 86.2 (±38.1) ng/ml, indicating a reduction of 28%. Bone mineral density Z-score, improved from -1.47 (±1.76) to -0.46 (±0.99) (69.7% reduction). Out of the 1,301 total administrations, our patients reported only 37 (2.8%) infusion-related adverse events which were mild and transitory. Conclusion: Taliglucerase alfa exhibits good efficacy and a safe profile in the treatment of children and adolescents with Type 1 Gaucher disease.

Exocrine pancreatic insufficiency and fat malabsorption related to pancreatectomy and other gastrointestinal surgery: A narrative review.

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.

Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa.

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.

Interplay between mitochondrial dysfunction and lysosomal storage: challenges in genetic metabolic muscle diseases with a focus on infantile onset Pompe disease.

Background: Pompe disease (PD) is a rare, progressive autosomal recessive lysosomal storage disorder that directly impacts mitochondrial function, leading to structural abnormalities and potentially culminating in heart failure or cardiogenic shock. The clinical course and molecular mechanisms of the disease remain incompletely understood. Methods: We performed a retrospective analysis to examine the clinical manifestations, genetic traits, and the relationship between PD and mitochondrial function in a pediatric patient. This comprehensive evaluation included the use of ultrasound echocardiograms, computed tomography (CT) scans, electrocardiograms, mutagenesis analysis, and structural analysis to gain insights into the patient's condition and the underlying mechanisms of PD. For structural analysis and visualization, the structure of protein data bank ID 5KZX of human GAA was used, and VMD software was used for visualization and analysis. Results: The study revealed that a 5-month-old male infant was admitted due to fever, with physical examination finding abnormal cardiopulmonary function and hepatomegaly. Laboratory tests and echocardiography confirmed heart failure and hypertrophic cardiomyopathy. Despite a week of treatment, which normalized body temperature and reduced pulmonary inflammation, cardiac abnormalities did not show significant improvement. Further genetic testing identified a homozygous mutation c.2662G>T (p.E888) in the GAA gene, leading to a diagnosis of Infantile-Onset Pompe Disease (IOPD). Conclusions: Although enzyme replacement therapy can significantly improve the quality of life for patients with PD, enhancing mitochondrial function may represent a new therapeutic strategy for treating PD.

Women with Gaucher Disease.

Gaucher disease is an inherited disorder in which there is a deficiency of the enzyme glucocerebrosidase, which leads to the accumulation of glucosylceramide. Although much scientific evidence is now available, there is still limited data on the impact on the different life stages of women with this disease. Among other alterations, a delay in menarche has been described, although it has not been related to fertility problems. Menorrhagia is relatively frequent, being related to the presence of thrombocytopenia, thrombocytopathies or coagulation disorders. On the other hand, pregnancy planning is an increasingly frequent concern. All patients should undergo genetic counseling, and it is important to monitor the appearance or worsening of organomegaly, bone and hematologic abnormalities to establish clinical and therapeutic recommendations. Management during the puerperium will depend on the evolution of gestation, and, during the lactation period, the potential appearance of bone complications should be assessed. An early onset of menopause, compared to the general population, has also been described, which may accelerate the development of osteopenia. Finally, although the usual screening protocols for neoplasms are currently being performed, it is recommended to watch for early signs of liver or renal neoplasms when examining the results of imaging tests performed during evaluations for this disease.

Diagnosis of alpha-Mannosidosis: Practical approaches to reducing diagnostic delays in this ultra-rare disease.

Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent alpha-mannosidase in lysosomes, which leads to intracellular accumulation of mannose-containing oligosaccharides. Diagnosis of alpha-mannosidosis is often delayed, in part because of the rarity of the disease, its gradual onset and heterogeneity of presentation, but also because of the similarity of many signs and symptoms of the disease to those of other lysosomal diseases. Treatment of alpha-mannosidosis was previously limited to hematopoietic stem cell transplantation, but outcomes are variable and not all patients are eligible or have a suitable donor. Recently, an enzyme replacement therapy, recombinant human alpha-mannosidase (velmanase alfa), was approved for the treatment of non-neurological manifestations in adult and pediatric patients with alpha-mannosidosis. Treatment with velmanase alfa reduces serum levels of oligosaccharides, increases levels of immunoglobulin G, and improves patients' functional capacity and quality of life, although it is not effective for the neurologic phenotype because it does not cross the blood-brain barrier. Since the effects of velmanase alfa are more marked in children than adults, early diagnosis to allow early initiation of treatment has become more important. To support this, patient, parent/caregiver, and clinician awareness and education is imperative. A number of approaches can be taken to meet this goal, such as the development of disease registries, validated diagnostic algorithms, and screening tools, improved under-/post-graduate clinician education, easily accessible and reliable information for patients/families (such as that made available on the internet), and the formation of patient advocacy groups. Such approaches may raise awareness of alpha-mannosidosis, reduce the diagnostic delay and thus improve the lives of those affected.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Pegvaliase therapy for phenylketonuria: Real-world case series and clinical insights.

OBJECTIVE: The aim of this study is to present a series of case studies on the real-life use of pegvaliase in Italy in managing patients affected by phenylketonuria (PKU) and provide practical insight and support to healthcare professionals currently approaching and facing this novel enzyme substitution therapy. METHODS: A panel of 11 PKU experts from seven leading Italian treatment centers attended online virtual meetings with the aim of reviewing their clinical and practical experiences with pegvaliase based on occurred cases. In selecting the cases, specific consideration was given to the nationwide representation of the centers involved and to the number of patients with PKU managed. Cases were thoroughly reviewed, with comprehensive discussions enabling the identification of key take-home messages regarding pegvaliase therapy. RESULTS: The panel discussed 18 cases, 11 males and 7 females (age range 17-43 years). At the last follow-up (up to 111 weeks after pegvaliase initiation), 11 out of 18 patients (61%) reached Phe levels below 600 µmol/l. Outcomes varied significantly across cases. All cases underscore the potential of pegvaliase in reducing Phe levels, enhancing the quality of life, and promoting social skills and independence. Additionally, the cases highlight the challenges associated with pegvaliase therapy, including managing adverse events and ensuring patient motivation and adherence. CONCLUSION: This is the first report about the Italian experience of managing patients affected by PKU with pegvaliase. Given the limited real-world data on the use of pegvaliase in PKU management, this case series offers valuable insights into the practical implementation and management of pegvaliase therapy in this Country. Continued research and data collection will be crucial to confirm and progress with this treatment. Despite potential challenges, pegvaliase therapy represents a substantial promise in managing PKU in Italy. Patient education, personalized treatment approaches, and careful monitoring are important to ensure optimal patient outcomes.

Symptoms, burden, and unmet needs of patients living with exocrine pancreatic insufficiency: a narrative review of the patient experience.

Exocrine pancreatic insufficiency (EPI) stems from a deficiency of functional pancreatic enzymes with consequent maldigestion and malnutrition. EPI shares clinical symptoms and manifestations with other disorders and is a considerable burden to individuals affected. In this narrative review, we analyzed the literature to identify relevant publications on living with EPI with the scope of individuating evidence gaps, including those related to symptoms, health-related quality of life (HRQoL), emotional functioning, disease burden, presence of comorbidities, and the use of pancreatic enzyme replacement therapy (PERT). Abdominal pain emerged as one of the most prominent symptoms. HRQoL was affected in EPI, but no articles examined emotional functioning. Comorbidities reported involved other pancreatic disorders, diabetes, gastrointestinal disorders, sarcopenia and osteopenia, cardiovascular disorders, bacterial overgrowth, and nutritional deficiencies. PERT was found to be effective in improving EPI symptoms and was well tolerated by most individuals. Our review revealed a dearth of literature evidence on patients' experience with EPI, such as emotional functioning and disease burden. We also revealed that studies on long-term effects of PERT are missing, as are studies that would help advance the understanding of the disease and its progression, risk/mitigating factors, and comorbidities. Future studies should address these identified gaps.

Real-life impacts of olipudase alfa: The experience of patients and families taking an enzyme replacement therapy for acid sphingomyelinase deficiency.

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.

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa.

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months. Results: A total of n = 8/15 patients received alglucosidase for more than 3 years prior to switching, and n = 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8 U/L, -3.0 mmol/molCr, and -14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.