Intranasal Delivery of Adenoviral and AAV Vectors for Transduction of the Mammalian Peripheral Olfactory System

Uytingco, Cedric; Martens, Jeffrey R.

doi:10.1007/978-1-4939-9139-6_17

Cited by 5 publications

(5 citation statements)

References 42 publications

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“…In addition, intranasal administration directs the preparation directly to the bronchial tree without the first pass effect and the possible potential loss of genome copies of rAAV vectors in the body (42)(43)(44)(45)(46)(47)(48)(49). Our study indicated that transduction efficiency is influenced by the vector, promoter and route of administration as has also been shown by Belur et al (64) who have demonstrated that the CAG promoter is more effective (64).…”

Section: (A and C) Results Show The Transduction Efficiency Of The Rasupporting

confidence: 78%

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Mosaic Recombinant Adeno-associated Virus Vector rAAV/DJ/CAG for Targeted Gene Delivery to Melanoma Cells Metastasized to the Lung

et al. 2020

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Background/Aim: Patients with metastasized melanoma have limited treatment options and poor diagnosis. Therefore, the development of treatments requires a new therapeutic approach, of which gene therapy using rAAV vectors can be proposed. The aim of the study was to examine the efficiency of the rAAV vector to transduce mouse melanoma cells both in vitro and in vivo. Materials and Methods: Different rAAV serotypes encoding GFP under the control of both chicken beta-actin and cytomegalovirus promoters were used in the experiments. Intranasal, intraperitoneal, intravenous and intratumoral pathways of administration of rAAV vectors were tested using quantitative-PCR and immunohistochemical staining. Results: The highest transduction efficiency in metastatic cells in vivo was observed 7 days after intranasal administration of a 10 10 gc/0.03 ml dose of rAAV/DJ-CAG. Conclusion: Melanoma gene therapy based on rAAV vectors is a possible treatment option. Melanoma is a tumor that derives from pigment cellsmelanocytes, which develop from the neural tissue of integuments. The most common starting point of melanoma is the skin, but it may also be formed within the mucous membranes of the gastrointestinal tract or in the eyeball. It is a cancer with a high potential for metastasis (1, 2). Despite the progress in anti-cancer treatment, the number of deaths due to metastatic melanoma is still increasing and from the beginning of 2019 circa 7,000 patients in the USA died of it (1). Its aggressiveness causes as much as 90% of deaths among all skin cancers (3). The median survival of patients with melanoma who have distant metastases is shorter than 1 year (4). In the initial stage, the disease is curable, but unfortunately in the advanced stage, when metastasis occurs, it is practically incurable (5). The treatment, which has so far been proposed for the advanced stage, does not provide the desired benefit and the survival of these patients remains unsatisfactory. For instance, the annual survival rate after treatment with targeted therapy for the dual BRAF/MEK mutation is only about 50-60% (4, 6). Therefore, one of the future therapeutic approaches in the treatment of metastatic melanoma can be gene therapy using rAAV vectors, especially with the use of hybrid serotypes, which can achieve high efficiency of gene delivery (7-9). AAV viruses are non-pathogenic, small (approx. 25 nm in diameter) and infect both dividing and non-dividing cells. A distinguishing trait of rAAV is also the occurrence of various serotypes, which are characterized by strong tropism to selected cell types, making them ideal candidates for gene therapy (10). rAAV viruses have become increasingly popular in clinical trials (11, 12). In recent years, two pharmaceutical products using rAAV vectors-Glybera (13) and Luxturna (14) have been registered. Recent studies conducted on hybrid/mosaic serotypes have shown a greater transduction efficiency and are more heterogeneous, both in cellular and tissue specificity (15). The new rAAV vectors are created by a num...

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Section: (A and C) Results Show The Transduction Efficiency Of The Rasupporting

confidence: 78%

“…To understand the obtained results, one can refer to the specific anatomy of the respiratory system. Thanks to the highly vascularized nasal cavity, it is possible to quickly and directly introduce drugs, as well as gene preparations into the lungs (42,94).…”

Section: (A and C) Results Show The Transduction Efficiency Of The Ramentioning

confidence: 99%

Mosaic Recombinant Adeno-associated Virus Vector rAAV/DJ/CAG for Targeted Gene Delivery to Melanoma Cells Metastasized to the Lung

et al. 2020

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“…Following virus delivery, the mice were closely monitored for 30 min and the subsequent days. A detailed procedure of intra-nasal administration to transduce OSNs has been published ( Uytingco and Martens, 2019 ). Ten days after intranasal viral administration, mice were euthanized with CO 2 , decapitated, and the head was split along the cranial midline to expose the OE.…”

Section: Methodsmentioning

confidence: 99%

The role of a ciliary GTPase in the regulation of neuronal maturation of olfactory sensory neurons

et al. 2023

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Olfactory sensory neurons (OSNs) form embryonically and mature perinatally, innervating glomeruli and extending dendrites with multiple cilia. This process and its timing are crucial for odor detection and perception and continues throughout life. In the olfactory epithelium (OE), differentiated OSNs proceed from an immature (iOSN) to a mature (mOSN) state through well-defined sequential morphological and molecular transitions, but the precise mechanisms controlling OSN maturation remain largely unknown. We have identified that a GTPase, ARL13B, has a transient and maturation state-dependent expression in OSNs marking the emergence of a primary cilium. Utilizing an iOSN-specific Arl13b-null murine model, we examined the role of ARL13B in the maturation of OSNs. The loss of Arl13b in iOSNs caused a profound dysregulation of the cellular homeostasis and development of the OE. Importantly, Arl13b null OSNs demonstrated a delay in the timing of their maturation. Finally, the loss of Arl13b resulted in severe deformation in the structure and innervation of glomeruli. Our findings demonstrate a previously unknown role of ARL13B in the maturation of OSNs and development of the OE.

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“…The PLCδ1-PH domain binds to PI(4,5)P 2 with high affinity and, therefore, was applied to label the endogenous PI(4,5)P 2 ( 35 ). En face confocal imaging was performed 10 days after the virus infection ( 37 ). Previous laboratory work showed that the mature OSNs are the only neurons in the olfactory epithelium that can be infected by AV ( 38 ).…”

Section: Resultsmentioning

confidence: 99%

Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies

Xie¹,

Habif²,

Ukhanov³

et al. 2022

JCI Insight

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Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet-Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that PI(4,5)P2, a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration.Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of INPP5E restored cilia length, and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2 and F-actin-dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan therapeutic intervention targets for the treatment of ciliopathies.

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Intranasal Delivery of Adenoviral and AAV Vectors for Transduction of the Mammalian Peripheral Olfactory System

Cited by 5 publications

References 42 publications

Mosaic Recombinant Adeno-associated Virus Vector rAAV/DJ/CAG for Targeted Gene Delivery to Melanoma Cells Metastasized to the Lung

Mosaic Recombinant Adeno-associated Virus Vector rAAV/DJ/CAG for Targeted Gene Delivery to Melanoma Cells Metastasized to the Lung

The role of a ciliary GTPase in the regulation of neuronal maturation of olfactory sensory neurons

Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies

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