Optimization of AAV vectors to target persistent viral reservoirs

Colón-Thillet, Rossana; Jerome, Keith R.; Stone, Daniel

doi:10.1186/s12985-021-01555-7

Cited by 34 publications

(20 citation statements)

References 179 publications

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“…This effort has been spearheaded by the development of numerous AAV serotypes, isolated from humans, nonhuman primates, and other species. 18 AAV2 was the first serotype to be vectorized and has been pseudo-typed using the capsids of other AAVs. 19 This has expanded the cell types that can be infected by AAV, and, in turn, increased the efficacy of AAV-mediated gene therapy.…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

Mosca

Gomero

et al. 2021

Molecular Therapy - Methods & Clinical Development

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AAV-mediated gene therapy holds promise for the treatment of lysosomal storage diseases (LSDs), some of which are already in clinical trials. Yet, ultra-rare subtypes of LSDs, such as some glycoproteinoses, have lagged. Here, we report on a long-term safety and efficacy preclinical study conducted in the murine model of galactosialidosis, a glycoproteinosis caused by a deficiency of protective protein/cathepsin A (PPCA). One-month-old Ctsa −/− mice were injected intravenously with a high dose of a self-complementary AAV2/8 vector expressing human CTSA in the liver. Treated mice, examined up to 12 months post injection, appeared grossly indistinguishable from their wild-type littermates. Sustained expression of scAAV2/8- CTSA in the liver resulted in the release of the therapeutic precursor protein in circulation and its widespread uptake by cells in visceral organs and the brain. Increased cathepsin A activity resolved lysosomal vacuolation throughout the affected organs and sialyl-oligosacchariduria. No signs of hyperplasia or inflammation were detected in the liver up to a year of age. Clinical chemistry panels, blood cell counts, and T cell immune responses were normal in all treated animals. These results warrant a close consideration of this gene therapy approach for the treatment of galactosialidosis, an orphan disease with no cure in sight.

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Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

Mosca

Gomero

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…Many methods for intrabody delivery into target cells are available such as the delivery of intrabody genes by plasmids or viral transduction, or using polymeric and dendrimeric nanoparticles embedded with small hydrophobic and hydrophilic drugs, peptides, vaccines and antibodies [ 95 ]. The most promising and efficient methods for intrabody transduction and expression in cancer cells are the use of lipid nanoparticles with embedded mRNA [ 49 , 96 , 97 , 98 ] and transduction with a new generation of AAVs carrying the intrabody cDNA [ 45 , 47 ] ( Figure 4 ).…”

Section: Bringing Intrabodies Into Cancer Patients: Delivery Of Intra...mentioning

confidence: 99%

“…Recombinant AAV vectors are the most promising vectors for gene therapy. They are able to deliver gene-editing enzymes, RNA interference and antibodies [ 47 ]. AAV capsids have been generated with cell/tissue specificity, which demonstrated improved transduction efficiency and reduced immunogenicity.…”

Section: Bringing Intrabodies Into Cancer Patients: Delivery Of Intra...mentioning

confidence: 99%

Therapeutic Potential of Intrabodies for Cancer Immunotherapy: Current Status and Future Directions

Böldicke

2022

Antibodies

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Tumor cells are characterized by overexpressed tumor-associated antigens or mutated neoantigens, which are expressed on the cell surface or intracellularly. One strategy of cancer immunotherapy is to target cell-surface-expressed tumor-associated antigens (TAAs) with therapeutic antibodies. For targeting TAAs or neoantigens, adoptive T-cell therapies with activated autologous T cells from cancer patients transduced with novel recombinant TCRs or chimeric antigen receptors have been successfully applied. Many TAAs and most neoantigens are expressed in the cytoplasm or nucleus of tumor cells. As alternative to adoptive T-cell therapy, the mRNA of intracellular tumor antigens can be depleted by RNAi, the corresponding genes or proteins deleted by CRISPR-Cas or inactivated by kinase inhibitors or by intrabodies, respectively. Intrabodies are suitable to knockdown TAAs and neoantigens without off-target effects. RNA sequencing and proteome analysis of single tumor cells combined with computational methods is bringing forward the identification of new neoantigens for the selection of anti-cancer intrabodies, which can be easily performed using phage display antibody repertoires. For specifically delivering intrabodies into tumor cells, the usage of new capsid-modified adeno-associated viruses and lipid nanoparticles coupled with specific ligands to cell surface receptors can be used and might bring cancer intrabodies into the clinic.

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“…Adeno-associated virus (AAV) vectors can deliver antiviral therapeutics to hepatocytes for the treatment of HBV 36,37 . To determine whether HBV+ PHH in our model can be transduced by AAV vectors, we administered scAAV.LK03-smCBA-GFP or scAAV3B-smCBA-GFP, which have known tropism for PHH in liver-humanized FRG and NSG-PiZ mice respectively [56][57][58] , intravenously at doses of 1x10 12 , 2x10 11 and 2x10 10 vg/mouse to humanized NSG-PiZ mice that had been chronically infected with HBV for 142 days (n=3 per dose and serotype).…”

Section: Aav Transduction Of Hbv+ Phh In Liver Humanized Nsg-piz Micementioning

confidence: 99%

“…HBV+ NSG-PiZ mice can be followed longitudinally for at least 169 days and can be monitored for levels of human albumin (huAlb), HBsAg and viral loads, or for intra-hepatic viral DNA levels at necropsy. HBV+ mice are responsive to traditional RTi therapy, and HBV+ PHH can be transduced by hepatotropic AAV vector capsids, which is of particular importance for the study of novel gene therapies that target HBV 36, 37 . When taken together, our data demonstrates that liver humanized NSG-PiZ mice are a robust and comparatively inexpensive model that can be readily used to study the pathogenesis of CHB and antiviral therapies targeting ongoing CHB infections.…”

Section: Introductionmentioning

confidence: 99%

Liver humanized NSG-PiZ mice support the study of chronic hepatitis B virus infection and antiviral therapies

Colón-Thillet

Stone

Loprieno

et al. 2022

Preprint

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Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic hepatitis B (CHB) infection is established. Only humans and great apes are fully permissive to HBV replication, and this species restriction has impacted HBV research by limiting the utility of small animal models of HBV. To combat the species restriction of HBV and enable more HBV studies in vivo, liver-humanized mouse models have been developed that harbor primary human hepatocytes (PHH) and are fully permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV and can develop CHB. Mice were infected with a precore mutant clinical isolate that has now been serially passaged through 3 generations of mice without loss of fitness. HBV selectively replicates in hCK18+ human hepatocytes within chimeric livers, and HBV+ mice secrete infectious virions and HBsAg into blood, while also harboring covalently closed circular DNA (cccDNA). HBV+ mice remain viremic for at least 169 days, which should enable the study of new curative therapies targeting CHB and respond to antiviral entecavir therapy. The extended duration of viremia is sufficient to enable the study of established and new therapeutic approaches targeting CHB. Furthermore, HBV+ PHH in NSG-PiZ mice can be transduced by the hepatotropic AAV3b and AAV.LK03 vector capsids, which should enable the study of curative gene therapies that target CHB. In summary, our data demonstrates that liver humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing CHB models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy in a setting that is fully permissive to ongoing replication.

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Optimization of AAV vectors to target persistent viral reservoirs

Cited by 34 publications

References 179 publications

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

Therapeutic Potential of Intrabodies for Cancer Immunotherapy: Current Status and Future Directions

Liver humanized NSG-PiZ mice support the study of chronic hepatitis B virus infection and antiviral therapies

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