Recommendations for the Implementation of the Self-Administration of Alpha-1 Antitrypsin.

Purpose: Administration of exogenous alpha-1 antitrypsin (AAT) is the only specific therapy for the management of pulmonary morbidity in patients with AAT deficiency. It requires weekly or biweekly intravenous infusions, which may impact patient independence and quality of life. Self-administration of AAT therapy is an alternative to reduce the burden for patients who require AAT therapy. We presented herein experts' recommendations for the implementation of a program for the self-administration of AAT. Methods: This project was conducted using a modified nominal group technique and was undertaken in two online meetings involving the participation of 25 experts: specialists in pulmonology (n=17), nurses (n=5) and hospital pharmacists (n=3). Results: The following issues were discussed, and several recommendations were agreed upon on the following topics: a) patient profile and clinical evaluation, establishing selection criteria that should include clinical as well as social criteria; b) role of health care professionals, suggested roles for specialists in pulmonology, nurses, and hospital pharmacists; c) training by the nurse, including recommendations before initiating the training and the content of the training sessions; and d) logistic issues and follow-up, adherence, and patient support. Conclusion: We expect this proposal to increase awareness of this therapeutic alternative and facilitate the implementation of self-administration programs, thus contributing to optimizing the patient experience with AAT therapy. Further research on the outcomes of these programs, especially from the patient perspective, will also help to improve their design and implementation.

miR-320c Regulates SERPINA1 Expression and Is Induced in Patients With Pulmonary Disease.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3'UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease. METHODS: Firstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions. RESULTS: Overexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation. CONCLUSION: Our findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases.

New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients.

miR-320c Regulates SERPINA1 Expression and Is Induced in Patients With Pulmonary Disease.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3'UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease. METHODS: Firstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions. RESULTS: Overexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation. CONCLUSION: Our findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases.

Registro español de pacientes con déficit de alfa-1 antitripsina: evaluación de la base de datos y análisis de la población incluida / Spanish registry of patients with alpha-1 antitrypsin deficiency: database evaluation and population analysis

Introducción y objetivo: El Registro español de pacientes con déficit de alfa-1 antitripsina (REDAAT) se formó con el objetivo de mejorar el conocimiento sobre del DAAT. En este trabajo se evalúa el registro y se analiza la población de pacientes incluida en él. Métodos: Dispone de una base de datos alojada en la Web: www.redaat.es. Su base de datos recoge información clínica y funcional de individuos portadores de los fenotipos PiSZ, ZZ y variantes raras. Resultados: En la actualidad reúne información sobre 511 individuos procedentes de 103 centros sanitarios, gracias a la colaboración de 124 médicos. De ellos, 348 (74,2%) son homocigotos Pi*ZZ y 100 (19,5%) heterocigotos Pi*SZ. Existe una mayor concentración de casos en hospitales universitarios de tercer nivel. El 81% de los casos tiene enfermedad pulmonar y en menor proporción el DAAT se detectó por cribado familiar o enfermedad hepática. Se dispone de datos de seguimiento en el 45% de los casos, y un 35% recibieron tratamiento sustitutivo con alfa-1 antitripsina. Conclusiones: El REDAAT es una herramienta útil para obtener información de calidad sobre esta enfermedad minoritaria en condiciones de práctica clínica habitual, aunque obtener datos de seguimiento es difícil y no es posible conocer la representatividad de la muestra incluida

Introduction and objective: REDAAT, the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, was set up in order to improve knowledge of this disease. This study is an evaluation of the registry and an analysis of its patient population. Methods: The registry has a database hosted on the website www.redaat.es. It collects clinical and functional data on patients with PiSZ, ZZ phenotypes and other rare variants. Results: Thanks to the collaboration of 124 physicians, the registry currently contains information on 511 individuals from 103 healthcare centers. Of these 511, 348 (74.2%) are Pi*ZZ homozygotes, and 100 (19.5%) are Pi*SZ heterozygotes. More cases are seen in tertiary level hospitals. A total of 81% of the cases have respiratory disease, and a lower proportion of AATD cases were detected by family screening or liver disease. Follow-up data are available for 45% of the cases, and 35% received alpha-1 antitripsin replacement therapy. Conclusions: The REDAAT registry is a useful tool for obtaining quality information about this minority disease in routine clinical practice conditions, although it is difficult to obtain follow-up data, and the representativeness of the sample included cannot be determined

Spanish Registry of Patients With Alpha-1 Antitrypsin Deficiency: Database Evaluation and Population Analysis. / Registro español de pacientes con déficit de alfa-1 antitripsina: evaluación de la base de datos y análisis de la población incluida.

INTRODUCTION AND OBJECTIVE: REDAAT, the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, was set up in order to improve knowledge of this disease. This study is an evaluation of the registry and an analysis of its patient population. METHODS: The registry has a database hosted on the website www.redaat.es. It collects clinical and functional data on patients with PiSZ, ZZ phenotypes and other rare variants. RESULTS: Thanks to the collaboration of 124 physicians, the registry currently contains information on 511 individuals from 103 healthcare centers. Of these 511, 348 (74.2%) are Pi*ZZ homozygotes, and 100 (19.5%) are Pi*SZ heterozygotes. More cases are seen in tertiary level hospitals. A total of 81% of the cases have respiratory disease, and a lower proportion of AATD cases were detected by family screening or liver disease. Follow-up data are available for 45% of the cases, and 35% received alpha-1 antitripsin replacement therapy. CONCLUSIONS: The REDAAT registry is a useful tool for obtaining quality information about this minority disease in routine clinical practice conditions, although it is difficult to obtain follow-up data, and the representativeness of the sample included cannot be determined.