Adeno-Associated Virus Vector Gene Delivery Elevates Factor I Levels and Downregulates the Complement Alternative Pathway<i>In Vivo</i>

Ahmad, Amina; Mandwie, Mawj; Dreismann, Anna K; Smyth, Christine; Doyle, Helen; Malik, Talat H.; Pickering, Matthew C.; Lachmann, P. J.; Alexander, Ian E.; Logan, Grant J

doi:10.1089/hum.2021.022

Cited by 8 publications

(10 citation statements)

References 43 publications

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“…hHDM-FH is highly active, so relatively low (compared to levels used in the mouse herein) continuous production via gene therapy may reach therapeutic goals and in most cases the therapy would be correcting acquired or inherent deficits in FH function and not replacing it completely, where dosing at sufficient levels would need to be assured ( 92 ). An example of AAV-hHDM-FH therapy correcting an inherent deficit in the presence of normal FH levels is noted in the novel mouse model of FHR5 nephropathy ( 62 ) while FI has also been successfully delivered to the mouse liver, providing further proof of principal for such approaches ( 93 ). Indeed, a combination of FI and FH gene therapy approaches could be highly advantageous in some circumstances.…”

Section: Discussionmentioning

confidence: 99%

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

Kamala¹,

Malik²,

Hallam³

et al. 2021

Front. Immunol.

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C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1–5^18–20^R1–2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

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Section: Discussionmentioning

confidence: 99%

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

Kamala¹,

Malik²,

Hallam³

et al. 2021

Front. Immunol.

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“…Inhibition of liver‐derived FB expression resulted in decreased levels of MAC and angiogenic factors, vascular endothelial growth factor, and tumor growth factor β2, in the laser‐induced CNV model 89 . Taking the alternative approach, Logan and colleagues demonstrated that sustained increases in circulating FI could be achieved using AAV8 to target the liver; this induced a fourfold to fivefold increase in circulating FI levels and decrease in activity of the AP 90 . This FI gene therapy reduced the classic hallmarks of renal disease, C3 and IgG deposition, in a mouse model of systemic lupus erythematosus (NZBWF1), indicating an impact on the pathogenic process 90 …”

Section: Gene Therapies and Rnai Targeting The Complement System In P...mentioning

confidence: 99%

Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway

Dreismann

Hallam

Tam

et al. 2022

Immunological Reviews

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This review gives the reader a broad overview of the gene-targeting field including RNA targeting via RNA interference (RNAi) or antisense oligonucleotides (ASO), DNA targeting using clustered regularly interspaced short palindromic repeats (CRISPR) technology, and gene targeting via adeno-associated virus vectors (AAV). A brief overview for each technology is given, and the rationales for using gene targeting in alternative pathway-mediated diseases are highlighted. The review discusses current relevant clinical and preclinical applications and critically assesses challenges of gene targeting. To avoid overlap with other reviews elsewhere in this volume, only a brief introduction to complement or animal models in complement research is given and the reader will be referred to more substantial reviews.

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“…Although AAV vectors have been considered safe with low immunogenicity, recent reports have indicated adverse reactions such as liver injury, thrombotic microangiopathy, and degeneration of posterior ganglia in animal models due to the induction of immune responses when administered at high doses. 11,[24][25][26][27][28] Considering the systemic adverse reactions due to vectors, reducing the dose of vectors administered in the systemic injection is desirable. Arterial administration may prevent the distribution of vectors to organs other than the liver, because hepatic arterial administration results in the rapid disappearance of AAV in the blood.…”

Section: Discussionmentioning

confidence: 99%

Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

Kashiwakura

Endo

Ugajin

et al. 2022

Preprint

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Gene therapy for hemophilia using adeno-associated virus (AAV) vectors allows long-term coagulation factor expression. We examined the potential of a novel engineered liver-tropic AAV3B-based vector AAV.GT5 for hemophilia B gene therapy. In vitro transduction with AAV.GT5 in human hepatocytes was more than 100 times higher than with AAV-Spark100, while in vivo transduction efficacy into the liver and the increase in coagulation factor IX (FIX) antigen following intravenous injection of these vectors were similar in PXB mice (chimeric mice with a humanized liver) and macaques. The discrepancy was due to the low recovery and short half-life of AAV.GT5 in blood, depending on the positive charge of the heparin-binding site in the original AAV3B. The intra-hepatic vascular administration of AAV.GT5, but not AAV-Spark100, enhanced vector transduction into the liver and reduced vector distribution to the kidney in pigs. In macaques, the intra-hepatic artery injection of AAV.GT5 yielded a comparable increase in FIX antigen with a one-third dosage of peripheral venous administration. Two of four macaques who received AAV.GT5 intravenously did not develop neutralizing antibodies (NAbs) against AAV.GT5, while AAV-Spark100 induced serotype-specific NAbs in all four macaques. The NAb produced after the administration was relatively specific to the serotype and less responsive to the other serotype. As a result, the administration of AAV.GT5 successfully boosted FIX expression in one animal previously given AAV-Spark100. Thus, AAV.GT5 has different biodistribution and immunogenic characteristics compared with AAV-Spark100, and the intra-hepatic vascular administration may lessen the vector dose and avoid vector distribution to other organs.

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Adeno-Associated Virus Vector Gene Delivery Elevates Factor I Levels and Downregulates the Complement Alternative PathwayIn Vivo

Cited by 8 publications

References 43 publications

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway

Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

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