Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy

Schuh, Roselena Silvestri; Bidone, Juliana; Poletto, Édina; Pinheiro, Camila Vieira; Pasqualim, Gabriela; Carvalho, Talita Giacomet de; Farinon, Mirian; Diel, Dirnete; Xavier, Ricardo Machado; Baldo, Guilherme; Matte, Úrsula da Silveira; Teixeira, Hélder Ferreira

doi:10.1007/s11095-018-2503-5

Cited by 20 publications

(17 citation statements)

References 34 publications

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“…About 30 years ago, dextromorphan, also a lipid-soluble small molecule, was detected in brain tissue following the intranasal administration of the drug in small volumes, 5 µl, in rats (Char et al, 1992). Since then, the literature on the transnasal delivery of drugs to the brain has been extended to large molecules, including plasmid DNA for gene therapy (Oviedo et al, 2017;Schuh et al, 2018). There are important principles underlying nasal-to-brain drug delivery:…”

Section: Trans-nasal Drug Delivery To Brainmentioning

confidence: 99%

“…• Intra-nasal injury is caused by the administration of volumes >100 µl/nares in humans (Merkus et al, 2003), which must translate to volumes ≥10 µl/nares in rodents. One finds that in the majority of publications on nose-to-brain delivery, the volumes administered are so large that the test animal must be sedated and then placed in a reverse Trendelenburg position to accommodate the large volume of drug instilled into the nares (Schuh et al, 2018). Local nasal injury is the most likely mechanism by which large molecule drugs gain access to olfactory CSF following nasal instillation.…”

Section: Trans-nasal Drug Delivery To Brainmentioning

confidence: 99%

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Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

Pardridge

2020

Front. Aging Neurosci.

265

200

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Alzheimer's disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The presence of BBB delivery technology allows for engineering the therapeutic to enable entry into the brain across the BBB from blood. Brain drug development may still take place in the absence of BBB delivery technology, but with a reliance on approaches that have rarely led to FDA approval, e.g., CSF injection, stem cells, small molecules, and others. CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood. A CSF injection of a drug is equivalent to a slow intravenous (IV) infusion of the pharmaceutical. Given the profound effect the existence of the BBB has on brain drug development, future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.

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Section: Trans-nasal Drug Delivery To Brainmentioning

confidence: 99%

Section: Trans-nasal Drug Delivery To Brainmentioning

confidence: 99%

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

Pardridge

2020

Front. Aging Neurosci.

265

200

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Section: Mps I Gene Therapy Strategiesmentioning

confidence: 99%

“…Nanocarriers have been investigated as a nonviral gene therapy to deliver nucleic acids 58,59 . Schuh et al used nanoemulsions, polymers that interact with biological membranes to promote internalization of the attached nucleic acids, to deliver the IDUA cDNA to the CNS through the nasal passages 58 . When comparing treated mice to an untreated control group, a twofold increase of IDUA activity in brain tissue was observed along with marginal IDUA activity in the spleen and kidney, likely from drainage of the nasal passages leading to DNA integration into other areas 58 .…”

Section: Mps I Gene Therapy Strategiesmentioning

confidence: 99%

Mucopolysaccharidoses type I gene therapy

Hurt

Dickson

Curiel

2021

J of Inher Metab Disea

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Mucopolysaccharidoses type I (MPS I) is an inherited metabolic disease characterized by a malfunction of the α‐l‐iduronidase (IDUA) enzyme leading to the storage of glycosaminoglycans in the lysosomes. This disease has longtime been studied as a therapeutic target for those studying gene therapy and many studies have been done using various vectors to deliver the IDUA gene for corrective treatment. Many vectors have difficulties with efficacy and insertional mutagenesis concerns including adeno‐associated viral (AAV) vectors. Studies of AAV vectors treating MPS I have seemed promising, but recent deaths in gene therapy clinical trials for other inherited diseases using AAV vectors have left questions about their safety. Additionally, the recent modifications to adenoviral vectors leading them to target the vascular endothelium minimizing the risk of hepatotoxicity could lead to them being a viable option for MPS I gene therapy when coupled with gene editing technologies like CRISPR/Cas9.

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“…Human fibroblasts were used as neuronal-type cells. In fact, fibroblasts were often chosen instead of brain cells due to the high difficulty in primary glial and neuronal cells culture [ 34 ]. Furthermore, fibroblasts usually are in the olfactory bulb, olfactory mucosa, and meninges [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles

et al. 2021

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The nose-to-brain delivery route is used to bypass the blood–brain barrier and deliver drugs directly into the brain. Over the years, significant signs of progress have been made in developing nano-drug delivery systems to address the very low drug transfer levels seen with conventional formulations (e.g., nasal solutions). In this paper, sericin nanoparticles were prepared using crocetin as a new bioactive natural cross-linker (NPc) and compared to sericin nanoparticles prepared with glutaraldehyde (NPg). The mean diameter of NPc and NPg was about 248 and 225 nm, respectively, and suitable for nose-to-brain delivery. The morphological investigation revealed that NPc are spherical-like particles with a smooth surface, whereas NPg seem small and rough. NPc remained stable at 4 °C for 28 days, and when freeze-dried with 0.1% w/v of trehalose, the aggregation was prevented. The use of crocetin as a natural cross-linker significantly improved the in vitro ROS-scavenging ability of NPc with respect to NPg. Both formulations were cytocompatible at all the concentrations tested on human fibroblasts and Caco-2 cells and protected them against oxidative stress damage. In detail, for NPc, the concentration of 400 µg/mL resulted in the most promising to maintain the cell metabolic activity of fibroblasts higher than 90%. Overall, the results reported in this paper support the employment of NPc as a nose-to-brain drug delivery system, as the brain targeting of antioxidants is a potential tool for the therapy of neurological diseases.

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Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy

Cited by 20 publications

References 34 publications

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

Mucopolysaccharidoses type I gene therapy

Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles

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