Gene therapy for neuronopathic mucopolysaccharidoses : state of the art

The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed

Gene Therapy for Neuronopathic Mucopolysaccharidoses: State of the Art

Virus adeno associat; Lentivirus; Vectors viralsVirus adenoasociado; Lentivirus; Vectores viralesAdeno-associated virus; Lentivirus; Viral vectorsThe need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed.This research received no external funding

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey

Malalties metabòliques hereditàries; Malaltia rara; Procés de transicióEnfermedades metabólicas hereditarias; Enfermedad rara; Proceso de transición:esInherited metabolic disease(s); Rare disease; Transition processInherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called “transition.” The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.This work was generated within the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), co-funded by the European Union within the framework of the Third Health Programme ERN-2016 - Framework Partnership Agreement 2017–2021, Project ID No. 739543

Implementation of second-tier tests in newborn screening for the detection of vitamin B12 related acquired and genetic disorders: results on 258,637 newborns

Homocisteïna; Cribratge de nounats; Deficiència de vitamina B12Homocisteína; Cribado de recién nacidos; Deficiencia de vitamina B12Homocysteine; Newborn screening; Vitamin B12 deficiencyBackground Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B12 deficiency have been detected by clinical symptoms and only few of them trough NBS programs. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions. Methods A screening strategy using the usual primary markers followed by the analysis of MMA, MCA and Hcys as second tier-test in the first dried blood spot (DBS) was developed and evaluated. Results During the period 2015–2018 a total of 258,637 newborns were screened resulting in 130 newborns with acquired vitamin B12 deficiency (incidence 1:1989), 19 with genetic disorders (incidence 1:13,613) and 13 were false positive. No false negatives were notified. Concerning the second-tier test, the percentage of cases with MMA above the cut-off levels, both for genetic and acquired conditions was very similar (58% and 60%, respectively). Interestingly, the percentage of cases with increased levels of Hcys was higher in acquired conditions than in genetic disorders (87% and 47%, respectively). In contrast, MCA was high only in 5% of the acquired conditions versus in 53% of the genetic disorders, and it was always very high in all patients with propionic acidemia. Conclusions When screening for methylmalonic acidemia and homocystinuria, differential diagnosis with acquired vitamin B12 deficiency should be done. The results of our strategy support the inclusion of this acquired condition in the NBS programs, as it is easily detectable and allows the adoption of corrective measures to avoid the consequences of its deficiency

Impact of COVID19 pandemic on patients with rare diseases in Spain, with a special focus on inherited metabolic diseases

Inherited metabolic disease; Quality of life; Rare diseasesEnfermedad metabólica hereditaria; Calidad de vida; Enfermedades rarasMalaltia metabòlica hereditària; Qualitat de vida; Malalties raresIntroduction The Covid-19 pandemic soon became an international health emergency raising concern about its impact not only on physical health but also on quality of life and mental health. Rare diseases are chronically debilitating conditions with challenging patient care needs. We aimed to assess the quality of life and mental health of patients with rare diseases in Spain, with a special focus on inherited metabolic disorders (IMD). Methods A prospective case-control study was designed, comparing 459 patients suffering from a rare disease (including 53 patients with IMD) and 446 healthy controls. Quality of life (QoL) and mental health were assessed using validated scales according to age: KINDL-R and the Pediatric Symptom Checklist (PSC) for children and the WhoQoL-Bref questionnaire, GAD and PHQ-9 in adults. Results First, children and adults (but not adolescents) with IMD showed greater psychological effects than controls (p = 0.022, p = 0.026 respectively). Second, when comparing QoL, only adult patients with IMD showed worse score than controls (66/100 vs 74,6/100 respectively, p = 0.017). Finally, IMD had better quality of life than other rare neurological and genetic diseases (p = 0.008) or other rare diseases (p < 0.001 respectively) but similar alteration of the mental status. Conclusions Our data show that the pandemic had a negative impact on mental health that is more evident in the group of patients with IMD. Young age would behave as a protective factor on the perception of QoL. Furthermore, patients with IMD show a better QoL than other rare diseases

The LINCE Project: A Pathway for Diagnosing NCL2 Disease

NCL2 disease; Dried blood spot; Enzymatic activityEnfermedad de NCL2; Mancha de sangre seca; Actividad enzimáticaMalaltia de NCL2; Taca de sang seca; Activitat enzimàticaIntroduction: Neuronal Ceroid Lipofuscinosis (NCL) comprises a clinically and genetically heterogeneous group of 13 neurodegenerative lysosomal storage disorders. Neuronal Ceroid lipofuscinosis type 2 disease (NCL2), caused by the deficient lysosomal enzyme tripeptidyl peptidase 1 (TPP1), is the only one with an approved enzyme replacement treatment (ERT). Early initiation of ERT appears to modify significantly the natural history of the disease. We aimed to shorten the time to diagnosis of NCL2. Methods: In March 2017, we started per first time in Spain a selective screening program, the LINCE project, in pediatric patients with clinical symptoms compatible with NCL2 disease. The program covered the whole country. We distributed kits to pediatricians with the necessary material to assess patients. All samples in this study were received within one week of collection. Enzymatic activity determined on dried blood spots was the main method used to screen for TPP1 and palmitoyl protein thioesterase 1 (PPT1) for the differential diagnosis with neuronal ceroid lipofuscinosis type 1 (NCL1). Results: Over a period of three years, we received 71 samples. The analysis was minimally invasive, relatively cheap and fast-executing. Three cases identified as a direct result of the selective screening strategy were confirmed by genetic study of NCL2 disease with a median age of 4.5 years. Our screening method has a specificity of 100%, and, with the absence to date of false negatives. We did not detect any NCL1-positive cases. Conclusions: LINCE proved to be a simple, useful, and reliable tool for the diagnosis of NCL2, enabling clinicians to diagnose NCL2 faster. The presence of NCL2-positive cases in our population and availability of treatment may facilitate the inclusion of NCL2 in neonatal screening programs for early diagnosis.This study received funding from Grant Biomarin Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.

Abstract Background Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. Methods Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. Results A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8–47.8 months) and untreated controls (n = 7; age, 12.6–45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. Conclusion rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. Trial registration ClinicalTrials.gov NCT02060526 ; EudraCT 2013-003450-24

Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain

Clinical practice; Glycerol phenylbutyrate; Urea cycle disordersPráctica clinica; Fenilbutirato de glicerol; Trastornos del ciclo de la ureaPràctica clínica; Fenilbutirat de glicerol; Trastorns del cicle de la ureaBackground and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.This study was funded by AECOM (Spanish Association for the Study of Inborn Errors of Metabolism). Immedica Pharma Spain funded medical writing support and article processing charges

Implementation of programmes for the transition of adolescents to adult care

Transición; Adultos jóvenes; Enfermedades crónicasTransition; Young adults; Chronic diseasesTransició; Adults joves; Malalties cròniquesHasta un 15-20% de adolescentes tienen algún problema de salud crónico. La adolescencia representa un periodo de riesgo especial para la evolución de las enfermedades crónicas, tanto en aquellos con padecimientos con mayor prevalencia como en los afectados por enfermedades raras. La transición de la asistencia pediátrica a la adulta empieza con la preparación y capacitación del paciente pediátrico, acostumbrado a los cuidados tutelados, para que asuma la responsabilidad de su autocuidado en una unidad de adultos. La transferencia es el momento en el que la persona joven pasa a los servicios de adultos y es dada de alta de los servicios pediátricos. La transición sólo se completa cuando los jóvenes están integrados y funcionan con total competencia dentro del servicio de adultos. Los profesionales de adultos tienen un rol crucial al momento de recibir e integrar a los adultos jóvenes. Un programa de transición puede incluir transiciones de diferente complejidad, desde enfermedades frecuentes y conocidas como el asma, que requieren un proceso más sencillo, hasta enfermedades raras complejas con necesidad de participación de personal muy especializado. La transición requiere un trabajo en equipo con participación de numerosos profesionales: pediatras y médicos de adultos, enfermeras, psicólogos clínicos, trabajadores sociales sanitarios, equipo de Farmacia, y personal administrativo. Es importante implicar a los adolescentes en la toma de decisiones y que los padres los dejen ir progresivamente. Un programa de transición bien estructurado puede mejorar los resultados en salud, la experiencia del paciente y la utilización y coste de los cuidados sanitarios.Up to 15%–20% of adolescents have a chronic health problem. Adolescence is a period of particular risk for the development or progression of chronic diseases for both individuals with more prevalent conditions and those affected by rare diseases. The transition from paediatric to adult care begins with preparing and training the paediatric patient, accustomed to supervised care, to assume responsibility for their self-care in an adult care setting. The transition takes place when the young person is transferred to adult care and discharged from paediatric care services. It is only complete when the youth is integrated and functioning competently within the adult care system. Adult care providers play a crucial role in welcoming and integrating young adults. A care transition programme can involve transitions of varying complexity, ranging from those required for common and known diseases such as asthma, whose management is more straightforward, to rare complex disorders requiring highly specialized personnel. The transition requires teamwork with the participation of numerous professionals: paediatricians and adult care physicians, nurses, clinical psychologists, health social workers, the pharmacy team and administrative staff. It is essential to involve adolescents in decision-making and for parents to let them take over gradually. A well-structured transition programme can improve health outcomes, patient experience, the use of health care resources and health care costs

Leigh syndrome associated with TRMU gene mutations

Insuficiència hepàtica aguda: Síndrome de Leigh; TRMUInsuficiencia hepática aguda; Síndrome de Leigh; TRMUAcute liver failure; Leigh syndrome; TRMUtRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease.This work was partially supported by the Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofounded with ERDF funds (Grant No. FIS PI15/01428, PI19/01772)