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PubMed1976

Isolation, chemical, and physical properties of alpha-1-antitrypsin.

A method of isolation of alpha-1-antitrypsin (alpha-1-AT) in good yield from normal human plasma is described. A key step was affinity chromatography employing an antiserum which had been depleted of alpha-1-AT antibodies. The final preparations were homogeneous by immunological and physicochemical criteria. The specific activity of the purified alpha-1-AT was 0.363 mg of active bovine trypsin inhibited per 1.0 mg of inhibitor. Polyacrylamide gel patterns at both alkaline and acid pH of highly pure preparations frequently, but not invariably, showed multiple hands. Molecular weight studies by sedimentation equilibrium ultracentrifugation in aqueous buffer and in 6 M guanidine as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis suggest that alpha-1-AT is a single polypeptide chain having a molecular weight of 49,500. Other physical and chemical properties of the inhibitor are described. A limited N-terminal sequence (Glu-Asp-Pro-Gln-Gly-Asx-Ala-Ala) was obtained. It was found that alpha-1-AT easily forms polymers and higher aggregates when exposed to denaturing agents such as 8 M urea and 6 M guanidine. The results suggest that aggregation is determined by both covalent and noncovalent forces.

Amino Acid Sequence↗
PubMed2026

Loss of the Mechanistic Target of Rapamycin Complex 1 Causes a Lethal Alpha-1 Antitrypsin Deficiency-Associated Liver Disease.

BACKGROUND & AIMS: SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin and lead to the proteotoxic alpha-1 antitrypsin deficiency-related liver disease. As mechanistic target of rapamycin is a key coordinator of proteostasis, we studied its role in alpha-1 antitrypsin deficiency-related liver disease. METHODS: PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mechanistic target of rapamycin or rapamycin-insensitive companion of mammalian target of rapamycin, corresponding to mechanistic target of rapamycin complexes 1 or 2, or with mice lacking mechanistic target of rapamycin. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations. RESULTS: At 2 months of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and mortality despite diminished hepatic alpha-1 antitrypsin accumulation. PiZ-RaptorΔhep animals displayed increased levels of the proapoptotic protein C/EBP homologous protein, but C/EBP homologous protein ablation did not rescue the phenotype. Serum proteomics revealed no signs of advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and small metabolite measurement demonstrated a metabolic reprogramming of PiZ-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals. CONCLUSIONS: In summary, in alpha-1 antitrypsin deficiency-related proteotoxic liver injury, regulatory-associated protein of mechanistic target of rapamycin preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.

Animals↗
PubMed2024

Editing Approaches to Treat Alpha-1 Antitrypsin Deficiency.

TOPIC IMPORTANCE: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder most commonly due to a single G to A point mutation (E342K), leading to debilitating lung and/or liver disorders and is associated with increased mortality. The E342K point mutation causes a conformational change of the AAT protein resulting in its retention in liver hepatocytes. This reduces AAT secretion into the serum resulting in higher protease activities due to the lack of inhibition from AAT, causing damage to healthy lung tissue. The current standard of care for lung manifestations involves weekly IV augmentation therapy and is considered suboptimal for these patients. Furthermore, there is currently no approved treatment for liver manifestations. The unmet medical need for patients with AAT deficiency remains high, and new treatment options are needed to treat the underlying disease etiology. REVIEW FINDINGS: Advances in genomic medicines may enable treatment by editing the DNA or RNA sequence to produce wild-type AAT instead of the mutated AAT caused by the E342K mutation. One approach can be achieved by directing endogenous adenosine deaminases that act on RNA to the E342K RNA site, where they catalyze adenosine to inosine conversion through a process known as RNA editing. The A-I RNA change will be read as a G during protein translation, resulting in an altered amino acid and restoration of wild-type AAT secretion and function. SUMMARY: In this review, we will discuss the pathophysiology of AAT deficiency and emerging treatment options with particular focus on RNA editing as a disease-modifying treatment for both liver and lung disease.

alpha 1-Antitrypsin Deficiency↗
PubMed2026

p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.

Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients who are homozygotes for the allele expressing Z-AAT were found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.

AATD↗
PubMed2026

ALPHA-1 antitrypsin genotype, sex, and lung cancer: Clinical and molecular characterisation.

INTRODUCTION AND OBJECTIVES: Alpha-1 antitrypsin deficiency is associated with lung and liver disease, but its role in lung carcinogenesis remains unclear. This study aimed to compare the clinical, functional, and molecular characteristics of lung cancer according to alpha-1 antitrypsin (AAT) genotype and, additionally, to explore differences by sex and the possible influence of environmental exposures. PATIENTS AND METHODS: We conducted a cross-sectional, single-centre study including 407 patients with incident lung cancer diagnosed between 2020 and 2023. Clinical, functional, radiological, molecular, and environmental variables were collected. Comparisons were performed between carriers and non-carriers of altered AAT alleles and between women and men. RESULTS: Of the 394 patients with available genotyping, 24.4% carried at least one altered allele. No significant differences were observed by genotype in smoking status, radon exposure, comorbidities, lung function, or histological subtype. Carriers showed significantly lower serum AAT levels and a higher frequency of values&#x2009;<&#x2009;116&#x2009;mg/dL (p&#x2009;<&#x2009;0.001). PD-L1 expression&#x2009;&#x2265;&#x2009;50% was more common in carriers (28.1% vs. 19.4%; p&#x2009;=&#x2009;0.036). In the multivariable analysis, the altered AAT genotype remained independently associated with a higher probability of PD-L1 expression&#x2009;&#x2265;&#x2009;50% (aOR&#x2009;=&#x2009;2.04; 95% CI: 1.09-3.80; p&#x2009;=&#x2009;0.026). Women had lower cumulative tobacco exposure, lower prevalence of emphysema and COPD, greater biomass exposure, higher frequency of adenocarcinoma, and more EGFR mutations (p&#x2009;<&#x2009;0.001). CONCLUSIONS: Patients carrying altered AAT alleles did not exhibit a distinctly different clinical profile, although they showed higher PD-L1 expression (&#x2265;50%). Furthermore, significant differences were observed between women and men in terms of exposure, histology and molecular alterations.

Humans↗
PubMed2026

Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.

Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.

Humans↗
PubMed1978

Separator isoelectric focusing for identification of alpha-1-antitrypsin (Pi M) subtypes.

A modified analytical isoelectric focusing procedure on polyacrylamide gel slabs, offering increased resolving capacity, has been developed for identification of six subtypes of the most common alpha-1-antitrypsin (A-1-AT) phenotype, Pi M. Combination of commercial Ampholine and other ampoteric substances, so called separators, produces pH plateaus, determined by the properties of the the additatives. Equilibrium is reached after extended focusing time, whereby stabilization of A-1-AT through alkylation is advantagous. The significance of this high resolution method for applications of the Pi system in genetic studies, and the general relevance of the modifications for other analytical purposes are discussed. A new nomenclature recommendation is presented.

Humans↗
PubMed1979

Polypoid gastric heterotopy of the small intestine in a patient with primary hyperparathyroidism and alpha-1-antitrypsin deficiency belonging to a MEA-family. With particular reference to the ultrastructure of the epithelial cells.

A patient with a solitary polypoid gastric heterotopy in the jejunum and severe bleeding as a complication is described. Previous reports on this rare disorder and the conditions of its development are discussed. The patient belongs to a family with multiple endocrine adenomatosis (MEA), some members of which had an alpha-1-antitrypsin deficiency. The association between the familial disease and the gastric heterotopy in this case might be another argument for the assumed congenital nature of the latter. The polyp was studied by means of light and electron microscopy. It was mostly lined by fundic mucosa and only partially by antral mucosa. Focal foveolar hyperplasia, cysts and lymphoplasmacellular infiltration of the mucosa are regarded as secondary tissue alteration. Parietal cells, chief and endocrine cells were identified. The parietal cells were in the nonsecreting state and appeared in two distinct forms which are described in detail.

Adult↗
PubMed1979

Synthesis of highly diversified carrier ampholytes. Evaluation of the resolving power of isoelectric focusing in the Pi system (alpha-1-antitrypsin genetic polymorphism).

The use of condensing reagents such as epoxypropanol, diepoxyoctane, acrylamide and N,N'-methylenebisacrylamide in the synthesis of carrier ampholytes increased the diversity of amphoteric components. The quality of these synthetic carrier ampholytes has been tested in the separation of variants of alpha-1-anti-trypsin, a genetic polymorphism called the Pi system. A resolving power of the order of 0.005 pH unit was obtained.

Ampholyte Mixtures↗
PubMed1977

Immunofixation after electrofocusing: improved method for specific detection of serum proteins with determination of isoelectric points. I. Immunofixation print technique for detection of alpha-1-protease inhibitor.

An improved method is described for direct localization of human serum proteins in polyacrylamide gel with simultaneous determination of their isoelectric points (pI). The technique employs isoelectric focusing in thin-layer polyacrylamide gels to separate the serum proteins and the pH gradient is read at 4 degrees C with a dual-membrane surface microelectrode. Subsequently, the desired proteins are localized by immunofixation in the gel or by immunofixation-printing onto cellulose acetate strips soaked in specific antiserum. No sectioning of the electrofocused gel is necessary, and the entire technique can be completed in less than 14 h. When this method is applied to the detection of the genetic variants of alpha-1-antitrypsin (alpha-1-protease inhibitor) (A1Pi system), the results indicate that it can be used to specifically localize serum proteins whose pI's differ by as little as 0.01 pH units. The resolution afforded is especially evident in the analysis of A1Pi M variants.

Blood Proteins↗
PubMed1977

Low pH stability of alpha-1-antititrypsin.

According to the previous findings of others, the trypsin inhibitory capacity of alpha-1-antitrypsin is irreversibly lost in acidic solutions below pH 5.0. In contrast, experiments reported herein show that considerable inhibitory activity can be regenerated as a time-dependent phenomena following titration to basic media. The rate of recovery of activity is accompanied by a decreasing amplitude in the fluorescent emission spectrum at 335 nm of acidified alpha-1-antitrypsin solutions following adjustment to pH 8.0. Acidic media also results in the slow, progressive formation of protein aggregates as measured using Sephadex gel filtration. This latter process is more prominent at pH 4.0, near the isoelectric point of alpha-1-antitrypsin than at pH 3 or 2. Both monomer and polymeric forms of alpha-1-antititrypsin were isolated before or after adjustment to basic media. Isolated monomeric material shows a high recovery of biological and immunological activity; aggregate forms, however, are immunologically cross-reactive but show little enzyme inhibitory activity.

Animals↗
PubMed1975

Physiological studies in a large sibship with antitrypsin deficiency.

A large sibship demonstrated the severe consequences of alpha-1 antitrypsin deficiency. Of II living sibs 6 were homozygous deficient (Pi type ZZ) and 5 heterozygous (Pi type MZ). The homozygous group showed severe obstructive ventilatory impairment by spirometry, marked abnormality of airway resistance and specific conductance with striking pulmonary hyperinflation. The heterozygous deficient group demonstrated a less severe obstructive defect by ventilation measurements with only marginal abnormality of airway resistance, specific conductance, and normal lung volumes. The evidence suggests that both the heterozygous and the homozygous states of alpha-1 antitrypsin deficiency are lung damaging.

Adolescent↗
PubMed2026

Base editing for precision therapeutics.

Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, &#x3b2;-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.

Humans↗
PubMed2026

Proteomic Immune Signatures of Severe HIV-Associated Tuberculosis in Sub-Saharan Africa: A Prospective, Multicenter Analysis From Uganda.

OBJECTIVES: Severe tuberculosis (TB) is a major cause of critical illness and death in people living with HIV (PLWH) worldwide. Despite this, the immunopathology of severe HIV-associated TB (HIV/TB) is poorly understood. We aimed to identify an immunopathologic signature of severe HIV/TB in sub-Saharan Africa. DESIGN AND SETTING: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, n = 241) and a rural validation cohort (Tororo, n = 253). PATIENTS: Adults (age &#x2265; 18 yr) hospitalized with severe febrile illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, severe HIV/TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-d mortality of 22% in the discovery cohort and 60-d mortality of 26% in the validation cohort). Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort as a supervised feature-selection approach to identify proteins associated with progressive HIV/TB phenotype. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-d mortality of 42% in the discovery cohort and 60-d mortality of 52% in the validation cohort). An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (lysosome-associated membrane glycoprotein 3), natural killer cell and T-cell stimulation and cytotoxicity (cluster of differentiation 70, class I-restricted T-cell-associated molecule), B-cell activation (immunoglobulin lambda constant 2), protease-mediated tissue injury (protease, serine 2 [trypsin-2]), dysregulated coagulation (serpin peptidase inhibitor, clade A [alpha-1 antitrypsin], member 5), extracellular matrix remodeling (epidermal growth factor-containing fibulin-like extracellular matrix protein 1), and growth hormone/insulin-like growth factor axis dysregulation (insulin-like growth factor binding protein 3). CONCLUSIONS: We identified an immunologic signature of severe HIV/TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.

Humans↗
PubMed2025

Emerging and potential use of CRISPR in human liver disease.

CRISPR is a gene editing tool adapted from naturally occurring defense systems from bacteria. It is a technology that is revolutionizing the interrogation of gene functions in driving liver disease, especially through genetic screens and by facilitating animal knockout and knockin models. It is being used in models of liver disease to identify which genes are critical for liver pathology, especially in genetic liver disease, hepatitis, and in cancer initiation and progression. It holds tremendous promise in treating human diseases directly by editing DNA. It could disable gene function in the case of expression of a maladaptive protein, such as blocking transthyretin as a therapy for amyloidosis, or to correct gene defects, such as restoring the normal functions of liver enzymes fumarylacetoacetate hydrolase or alpha-1 antitrypsin. It is also being studied for treatment of hepatitis B infection. CRISPR is an exciting, evolving technology that is facilitating gene characterization and discovery in liver disease and holds the potential to treat liver diseases safely and permanently.

Humans↗