4.3 Review

Gene therapy for alpha-1 antitrypsin deficiency: an update

Related references

Note: Only part of the references are listed.
Review Gastroenterology & Hepatology

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder

Malin Fromme et al.

Summary: Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, leading to the retention of AAT in liver cells and resulting in liver injury and lung disease. The Pi*ZZ genotype is responsible for severe AATD cases and can cause liver diseases in both children and adults. This review examines the relationship between genotypes and hepatic phenotypes, discusses the mechanisms of liver disease development, and explores diagnostic and therapeutic approaches for managing this disorder.

JOURNAL OF HEPATOLOGY (2022)

Article Medicine, Research & Experimental

Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease

Nan He et al.

Summary: Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease. This study used ferret models to demonstrate that complete loss of AAT and the most common mutation in AAT result in lung and hepatic diseases similar to those observed in AATD patients, making them a potential platform for preclinical testing of therapeutics including gene therapy.

JCI INSIGHT (2022)

Article Medicine, Research & Experimental

Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice

Marina Zieger et al.

Summary: This study demonstrates that gene therapy can be used to treat alpha(1)-antitrypsin deficiency, improving lung disease progression and restoring lung tissue elasticity and alveolar wall integrity.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2022)

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Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency

Pavel Strnad et al.

Summary: The trial demonstrated that fazirsiran treatment in patients with liver disease associated with AAT deficiency led to a significant reduction in Z-AAT concentrations in the liver and serum, as well as improvements in liver enzyme concentrations, showing potential therapeutic effects on liver fibrosis.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

Review Biotechnology & Applied Microbiology

Current Clinical Applications of In Vivo Gene Therapy with AAVs

Jerry R. Mendell et al.

Summary: Hereditary diseases are caused by gene mutations, affecting millions of Americans, and gene therapy using adeno-associated virus (AAV) has shown promise in treating these diseases. Five treatments have been approved for commercialization, with many more in clinical trials, showcasing the potential of gene therapy in treating a wide range of genetic disorders.

MOLECULAR THERAPY (2021)

Article Medicine, Research & Experimental

Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells

Motahareh Arjomandnejad et al.

Summary: Researchers have successfully simulated and modulated immune responses using AAV-CAR T cells and AAV-CAR Tregs, including inhibition of effector T cell activity and reduction of tissue inflammation, offering new insights into addressing immune limitations in AAV gene therapy.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2021)

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Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice

Pengpeng Liu et al.

Summary: The study introduces an NLS-optimized SpCas9-based prime editor that enhances genome editing efficiency and demonstrates the potential to induce tumor formation and correct pathogenic mutations in adult mice through somatic cell editing. The use of dual adeno-associated virus (AAVs) for delivery of a split-intein prime editor further establishes the capability of this system for in vivo installation of sequence modifications with important implications for disease modeling and correction.

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Review Immunology

T Cell-Mediated Immune Responses to AAV and AAV Vectors

Hildegund C. J. Ertl

Summary: Adeno-associated virus (AAV)-mediated gene transfer has shown benefits in treating patients with inherited diseases like hemophilia B, but challenges remain due to potential rejection of AAV-transduced cells. Immunosuppression may prevent rejection in some patients. CD8(+) T cells induced by AAV infections may recognize AAV vector's capsids and eliminate cells expressing degraded capsid antigens, or AAV vectors themselves may induce de novo T cell responses, particularly at high doses. This chapter discusses strategies to prevent activation of CD8(+) T cell responses to AAV infections and gene transfer.

FRONTIERS IN IMMUNOLOGY (2021)

Article Pharmacology & Pharmacy

Alpha1-antitrypsin deficiency: New therapies on the horizon

Katharina Remih et al.

Summary: AATD is caused by mutations in the SERPINA1 gene, with Pi*ZZ genotype being a major risk factor. Current treatment mainly focuses on AAT augmentation therapy for lung injury, with no medicinal products available for liver damage. Various approaches are being studied to address AAT production, folding, secretion, and degradation.

CURRENT OPINION IN PHARMACOLOGY (2021)

Review Pharmacology & Pharmacy

Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency

Martin R. Zamora et al.

Summary: AAT augmentation therapy is effective in slowing the progression of emphysema in patients with AAT deficiency, but cannot prevent end-stage lung disease. Lung and liver transplant are viable treatment options for end-stage disease, with favorable survival rates for patients with AATD. However, there are risks of post-transplant complications in AATD patients, particularly in cases of combined lung and liver transplantation.

THERAPEUTIC ADVANCES IN CHRONIC DISEASE (2021)

Review Pharmacology & Pharmacy

Alpha-1 antitrypsin deficiency research and emerging treatment strategies: what's down the road?

Franck F. Rahaghi

Summary: AAT deficiency is associated with emphysema, and intravenous AAT therapy has been proven to be clinically effective in slowing disease progression. However, the treatment is only recommended for the most severe cases of AATD, leaving many symptomatic individuals untreated. New, more cost-effective treatments are being sought to provide efficacy for less severe forms of the disease.

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Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

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Alpha1-Antitrypsin Deficiency

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In vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency

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