Evading and overcoming AAV neutralization in gene therapy

Earley, Joseph; Piletska, Elena; Ronzitti, Giuseppe; Piletsky, Sergey A.

doi:10.1016/j.tibtech.2022.11.006

Cited by 25 publications

(18 citation statements)

References 58 publications

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“…However, increasing evidence has shown that the high burden of intact and fragmented AAV DNA triggers prolonged DDR affecting the repopulation potential and graft clonal diversity in xenograft models ( 33 , 44 , 64 – 66 ). Although AAVs has been considered a nonintegrating platform, integration of inverted terminal repeats (ITRs) or full-length AAV DNA in on- and off-target sites ( 44 , 67 – 69 ) raised concerns for the possible impact of ITR transcription promoting activity on genes flanking insertions ( 44 , 61 , 70 – 75 ). We moved to the IDLV platform and achieved in the most primitive HSPC subset similar HDR efficiency obtained with the AAV6 platform, indicating the feasibility and potential advantage of IDLV.…”

Section: Discussionmentioning

confidence: 99%

Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Castiello,

Brandas,

Ferrari

et al. 2024

Sci. Transl. Med.

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Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of RAG1 achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human RAG1 in HSPCs from patients with hypomorphic RAG1 mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in Rag1 –/– mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.

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Section: Discussionmentioning

confidence: 99%

Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Castiello,

Brandas,

Ferrari

et al. 2024

Sci. Transl. Med.

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“…The immune system is then primed against this specific viral capsid and is ready to respond against potential re-administration. 64 Non-viral methods of gene therapy include small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), or clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genes (described in detail below). Non-viral vehicles currently used for CMTs include squalene-loaded nanoparticles 65 generated by chemical linkage of small molecules with squalene, a polyunsaturated hydrocarbon lipid.…”

Section: Viral and Non-viral Vehicles Employed In Gene Therapiesmentioning

confidence: 99%

“…Once cells are transduced by viral particles, a T‐cell mediated immune response is initiated that leads to B‐cell activation and the production of neutralizing antibodies. The immune system is then primed against this specific viral capsid and is ready to respond against potential re‐administration 64 …”

Section: General Aspects Of Gene Therapies For Cmt Neuropathiesmentioning

confidence: 99%

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Stavrou

Kagiava

Sargiannidou

et al. 2023

J Peripheral Nervous Sys

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Charcot–Marie–Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non‐virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene‐ and disease‐ and even mutation‐specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular‐genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non‐human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale‐up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.

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“…121 In addition to avoiding NAbs by limiting patient population, switching serotypes, or using engineered capsid variants, several strategies to remove existing antibodies have been proposed. 134 For example, it has been shown that multiple cycles of plasmapheresis greatly reduce AAV NAb levels in humans, 135 with a study in NHPs also demonstrating enhanced transduction after vascular delivery of AAV8 following 2 rounds of plasmapheresis. 136 Endopeptidase imlifidase-an IgG cleaving enzyme-has already been approved for HLA-sensitized kidney transplant patients and appeared effective in enhancing liver transduction in NHPs upon AAV readministration.…”

Section: Safety Aspects Of Aav-based Therapy Risks Of Immunogenicity ...mentioning

confidence: 99%

Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors

Khachigian

Varcoe

Suoranta

et al. 2023

ATVB

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Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected. PAD remains a growing global health problem as the population continues to age and diabetes incidence grows. Many patients with PAD, most notably those with critical limb ischemia, fail attempts at surgical and percutaneous intervention to improve blood flow and are at risk of amputation. Gene therapy provides an opportunity to change the clinical course of PAD in these patients via strategies that increase vascular supply through angiogenesis and arteriogenesis improving muscle perfusion and function in ischemic legs. This article discusses gene therapy approaches in the context of PAD, both intermittent claudication and critical limb ischemia, and the promise of adeno-associated virus–based strategies delivering not just VEGFs (vascular endothelial growth factors) but a range of other mediators as potential new therapeutics. We also highlight challenges and failures in the clinical translation of gene therapy for PAD and how at least some of these obstacles may be overcome using adeno-associated virus.

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Evading and overcoming AAV neutralization in gene therapy

Cited by 25 publications

References 58 publications

Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors

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