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Transgene Site-Specific Integration: Problems and Solutions

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Site-directed insertion of transgenes

Part of the book series: Topics in Current Genetics ((TCG,volume 23))

Abstract

Integrative gene transfer performed by viral and non-viral vectors have demonstrated their effectiveness, but have been linked to some adverse events, such as clonal expansion and tumorigenesis. These observations have raised serious concerns about the safety of gene transfer methods, and have led to many attempts to find new solutions. In this chapter, we summarize the major problems encountered with viral and non-viral-vectors and various ways of avoiding insertional mutagenesis, the induction of innate immunity and transgene silencing are described. We also list the main strategies for optimizing vector architecture so as to ensure safe and long-term expression of the transgene. Several new approaches have succeeded in targeting transgene integration to a specific locus using recombinases, homing endonucleases, zinc finger nucleases, integrases and transposases or a combination of them. Here, we report various criteria that can be used to define what is a good insertion site in the human genome.

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Abbreviations

ADA:

Adenosine deaminase deficiency

AAV:

Adeno-associated virus

CIS:

Common insertion site

DBD:

DNA binding domain

DSB:

Double-strand break

dsRNA:

double-stranded RNA

DTS:

DNA nuclear targeting sequence

EF1a:

Elongation factor-1a

ES:

Embryonic stem cells

iPS:

induced pluripotent stem

IRES:

Internal ribosome entry sequence

HAT:

Hypoxanthine aminopterin, and thymidine

LAM-PCR:

Linear amplification-mediated PCR

LINEs:

Long interspersed nuclear elements

LTR:

Long terminal repeat

LV:

Lentiviral vector

HE:

Homing endonuclease

HSS:

DNAseI-hypersensitive site

HR:

Homologous recombination

miRNAs:

microRNAs

MMLV:

Moloney murine leukemia virus

NHEJ:

Non-homologous end joining

NoLS:

Nucleolar localization sequence

nrLAM-PCR:

Non-restrictive LAM-PCR

PB:

PiggyBac

PGK:

Phosphoglycerate kinase

PRRs:

Pattern-recognition receptors

RISC:

RNA Induced Silencing Complex

γRV:

Gammaretroviruses

SB:

Sleeping Beauty

SIN:

Self-inactivating retrovirus

siRNAs:

small interfering RNAs

TFBS:

Transcription factor binding site

TLR:

Toll-like receptor

TSS:

Transcription start site

TIP-chip:

Transposon insertion site profiling chip

ZFN:

Zinc-finger nuclease

ZFP:

Zinc-finger protein

ZFR:

Zinc-finger recombinase

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  1. UFR des Sciences et Techniques, Université François Rabelais GICC, UMR CNRS 6239, Parc de Grandmont, 37200, Tours, France

    Solenne Bire

  2. UFR de Médicine, UMR CNRS 7292, GICC, Equipe LNOx “Niche leucémique & métabolisme oxydatif”, Université François Rabelais, Tours, France

    Florence Rouleux-Bonnin

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    Sylvaine Renault

  2. Cellectis SA, Rue de la Croix Jarry 8, Paris, 75013, France

    Philippe Duchateau

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Bire, S., Rouleux-Bonnin, F. (2013). Transgene Site-Specific Integration: Problems and Solutions. In: Renault, S., Duchateau, P. (eds) Site-directed insertion of transgenes. Topics in Current Genetics, vol 23. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4531-5_1

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