Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

Arjomandnejad, Motahareh; Dasgupta, Ishani; Flotte, Terence R.; Keeler, Allison M.

doi:10.1007/s40259-023-00585-7

Cited by 49 publications

(40 citation statements)

References 229 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This persistent moderate gliotic response of the cells after transduction by the virus was not observed in sham-injected eyes receiving PBS only. This finding underscores the current debate in the field that a thorough re-evaluation of the immunogenic potential of AAV serotypes and expression constructs used is necessary to optimize the efficacy of gene therapy approaches (Verdera et al 2020, Arjomandnejad et al 2023).…”

Section: Aav-vectored Gr Overexpression In Müller Cells Improves Neur...mentioning

confidence: 75%

The glucocorticoid receptor as a master regulator of Müller cell gliosis in the diabetic retina

Pfaller,

Kaplan,

Carido

et al. 2023

Preprint

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Müller glia cells are at the center of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Müller cell-specific signaling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Müller cells from diabetic db/db mice, we found the mRNA and protein expression of the glucocorticoid receptor (GR) to be significantly decreased, while its target gene cluster was down-regulated. Further, oPOSSUM TF analysis and ATAC- sequencing identified the GR as a master regulator of Müller cell gliosis in DR. Cortisol not only increased GR phosphorylation. It also induced changes in the expression of known GR target genes in retinal explants. Finally, retinal functionality was improved by AAV-mediated overexpression of GR in Müller cells. Our study demonstrates an important role of the glial GR in DR and implies that therapeutic approaches targeting this signalling pathway should be aimed at increasing GR expression rather than the addition of more ligand.

show abstract

Section: Aav-vectored Gr Overexpression In Müller Cells Improves Neur...mentioning

confidence: 75%

The glucocorticoid receptor as a master regulator of Müller cell gliosis in the diabetic retina

Pfaller,

Kaplan,

Carido

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…11 The AAV vector used in gene therapy has no discernible viral genome products to cause an immune response however the vector capsid is antigenic and has the potential to induce a reaction. 20 Capsid-specific CD8 + T cells can be triggered by hepatocytes which act as antigen-presenting cells by expressing capsid proteins on MHC class 1 receptors on the cell surface. 21 The recruitment of CD8 + T cells may occur through innate and adaptive immunity as there is supposed widespread exposure, in the human population to wild-type AAV vector serotypes, leading to individuals with preexisting AAV-neutralising antibodies.…”

Section: Immune Responses In Aav Associated Hepatitismentioning

confidence: 99%

Hepatitis after gene therapy, what are the possible causes?

Maina,

Foster

2024

Journal of Viral Hepatitis

View full text Add to dashboard Cite

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno‐associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune‐mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre‐existing liver conditions. Liver biopsy data conducted years post‐gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug‐induced liver injury (DILI) based on Hy's Law criteria. Essential pre‐therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non‐invasive fibroscans, while novel blood‐based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long‐term effects on the liver, providing insights for optimising gene therapy for haemophilia.

show abstract

“…Finally, more research is required to determine the possible side effects of the therapy in the cochlea in terms of inflammation and immunotoxicity. The immune response to AAVs in humans is still largely unknown [51], but ongoing clinical trials in the eye indicate that viral gene therapy may trigger an adaptive immune response [52][53][54].…”

Section: Gene-based Therapy For Hereditary Hearing Lossmentioning

confidence: 99%

Recent advances and future challenges in gene therapy for hearing loss

et al. 2023

View full text Add to dashboard Cite

Hearing loss is the most common sensory deficit experienced by humans and represents one of the largest chronic health conditions worldwide. It is expected that around 10% of the world's population will be affected by disabling hearing impairment by 2050. Hereditary hearing loss accounts for most of the known forms of congenital deafness, and over 25% of adult-onset or progressive hearing loss. Despite the identification of well over 130 genes associated with deafness, there is currently no curative treatment for inherited deafness. Recently, several pre-clinical studies in mice that exhibit key features of human deafness have shown promising hearing recovery through gene therapy involving the replacement of the defective gene with a functional one. Although the potential application of this therapeutic approach to humans is closer than ever, substantial further challenges need to be overcome, including testing the safety and longevity of the treatment, identifying critical therapeutic time windows and improving the efficiency of the treatment. Herein, we provide an overview of the recent advances in gene therapy and highlight the current hurdles that the scientific community need to overcome to ensure a safe and secure implementation of this therapeutic approach in clinical trials.

show abstract

Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer

Cited by 49 publications

References 229 publications

The glucocorticoid receptor as a master regulator of Müller cell gliosis in the diabetic retina

The glucocorticoid receptor as a master regulator of Müller cell gliosis in the diabetic retina

Hepatitis after gene therapy, what are the possible causes?

Recent advances and future challenges in gene therapy for hearing loss

Contact Info

Product

Resources

About