Modulation of coxsackie and adenovirus receptor expression for gene transfer to normal and dystrophic skeletal muscle

Larochelle, Nancy; Teng, Qingshan; Gilbert, Rénald; Deol, Jatinderpal R.; Karpati, George; Holland, Paul C.; Nalbantoglu, Joséphine

doi:10.1002/jgm.1433

Cited by 6 publications

(7 citation statements)

References 28 publications

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“…It has also been established that the abundance of myoblasts and myotubes as well as the relative abundance of CARs found in young mice contributes to greater transduction efficiency 42 53 54 . Further, the overexpression of CARs in muscle from adult transgenic mice has been shown to produce a significant increase in the transduction of skeletal muscle 55 56 . Taken together, these findings support the view that the reduced numbers of transduced motor neurons in adult mice is more than likely a consequence of the down-regulation of CARs observed throughout age.…”

Section: Discussionmentioning

confidence: 99%

Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

Tosolini

Morris

2016

Sci Rep

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Gene therapy can take advantage of the skeletal muscles/motor neurons anatomical relationship to restrict gene expression to the spinal cord ventral horn. Furthermore, recombinant adenoviruses are attractive viral-vectors as they permit spatial and temporal modulation of transgene expression. In the literature, however, several inconsistencies exist with regard to the intramuscular delivery parameters of adenoviruses. The present study is an evaluation of the optimal injection sites on skeletal muscle, time course of expression and mice’s age for maximum transgene expression in motor neurons. Targeting motor end plates yielded a 2.5-fold increase in the number of transduced motor neurons compared to injections performed away from this region. Peak adenoviral transgene expression in motor neurons was detected after seven days. Further, greater numbers of transduced motor neurons were found in juvenile (3–7 week old) mice as compared with adults (8+ weeks old). Adenoviral injections produced robust transgene expression in motor neurons and skeletal myofibres. In addition, dendrites of transduced motor neurons were shown to extend well into the white matter where the descending motor pathways are located. These results also provide evidence that intramuscular delivery of adenovirus can be a suitable gene therapy approach to treat spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

Tosolini

Morris

2016

Sci Rep

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“…As may be expected, these techniques focus on enhancing virus uptake rather than other processes essential to transduction. For instance, a complementary viral strategy can be used to boost the expression of the virus receptor(s) at peripheral nerve terminals that can then be therapeutically targeted with a different virus, as has been demonstrated with AAV-mediated CAR expression for increased AdV binding and uptake (Larochelle et al, 2010 ; Li et al, 2018b ). Receptor expression may also be selectively increased by genetic overexpression (Nalbantoglu et al, 2001 ) or administration of drugs that enhance transcription, albeit non-specifically (e.g., histone deacetylase inhibitors; Larochelle et al, 2010 ).…”

Section: Optimizing Intramuscular Gene Therapymentioning

confidence: 99%

“…For instance, a complementary viral strategy can be used to boost the expression of the virus receptor(s) at peripheral nerve terminals that can then be therapeutically targeted with a different virus, as has been demonstrated with AAV-mediated CAR expression for increased AdV binding and uptake (Larochelle et al, 2010 ; Li et al, 2018b ). Receptor expression may also be selectively increased by genetic overexpression (Nalbantoglu et al, 2001 ) or administration of drugs that enhance transcription, albeit non-specifically (e.g., histone deacetylase inhibitors; Larochelle et al, 2010 ). Similarly, genetic screens are beginning to identify a variety of viral restriction factors (i.e., proteins that constrain uptake and transduction), which could also be genetically or chemically manipulated, perhaps in a tissue-specific fashion, to aid uptake (Mano et al, 2015 ; Madigan et al, 2019 ).…”

Section: Optimizing Intramuscular Gene Therapymentioning

confidence: 99%

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Tosolini

Sleigh

2020

Front. Mol. Neurosci.

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Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses—adenovirus, adeno-associated virus (AAV), and lentivirus—and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.

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“…In any case, high levels of dystrophin expression seem to be required to reverse, at least partially, DMD pathology. Interestingly, Larochelle and collaborators injected AAV2 encoding CAR in adult mdx mice skeletal fibers and demonstrated that a moderate increase of CAR expression resulted in a significative increase of expression from Ad in skeletal muscle fibers [77], which could improve Ad-mediated DMD therapy and have a strong potential for non-regenerative skeletal muscle diseases.…”

Section: Gene Therapy To the Musclementioning

confidence: 99%

Helper Dependent Adenovirus Vectors: Progress and Future Prospects

Cots¹,

Bosch²,

Chillón

2013

CGT

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Sixteen years after Graham and coworkers described the most used system for generating helper-dependent adenovirus (HDAd) vectors, production systems have evolved considerably, and most resulting preparations have titres of 1 × 10(13) IU/ml (infection units/ml) and very low helper contamination levels (<0.1%). These advances in production, as well as the attractive characteristics of these vectors (large insert capacity and low cell immune response compared with first-generation Ad vectors) make them very interesting for many research purposes as they have become more accessible to the scientific community. In this review we summarise the latest strategies for producing HDAd vectors, describe the main areas of interest for which HDAd vectors are being used, and comment on the future prospects for HDAd vectors in gene therapy.

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Modulation of coxsackie and adenovirus receptor expression for gene transfer to normal and dystrophic skeletal muscle

Abstract: We have developed a method of increasing CAR levels in both normal and regenerating muscle.

Cited by 6 publications

References 28 publications

Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Helper Dependent Adenovirus Vectors: Progress and Future Prospects

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