Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain

Padmakumar, Smrithi; Jones, Gregory; Pawar, Grishma; Khorkova, Olga; Hsiao, Jane; Kim, Jonghan; Amiji, Mansoor M.; Bleier, Benjamin S.

doi:10.1016/j.jconrel.2021.01.027

Cited by 42 publications

(21 citation statements)

References 55 publications

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“…Remarkably, BDNF-AS -targeting antagoNATs were effectively delivered across the blood–brain barrier in a murine model utilizing a minimally invasive nasal depot (MIND). MIND is a medication delivery system that directs drug administration to the olfactory submucosal region and has achieved about 40% effectiveness compared to riskier invasive delivery methods ( Padmakumar et al, 2021 ). Such encouraging findings imply that lncRNA-based therapies will soon enter clinical testing.…”

Section: Discussionmentioning

confidence: 99%

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review

Sabaie

Amirinejad

Asadi

et al. 2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a heterogeneous degenerative brain disorder with a rising prevalence worldwide. The two hallmarks that characterize the AD pathophysiology are amyloid plaques, generated via aggregated amyloid β, and neurofibrillary tangle, generated via accumulated phosphorylated tau. At the post-transcriptional and transcriptional levels, the regulatory functions of non-coding RNAs, in particular long non-coding RNAs (lncRNAs), have been ascertained in gene expressions. It is noteworthy that a number of lncRNAs feature a prevalent role in their potential of regulating gene expression through modulation of microRNAs via a process called the mechanism of competing endogenous RNA (ceRNA). Given the multifactorial nature of ceRNA interaction networks, they might be advantageous in complex disorders (e.g., AD) investigations at the therapeutic targets level. We carried out scoping review in this research to analyze validated loops of ceRNA in AD and focus on ceRNA axes associated with lncRNA. This scoping review was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was conducted to find eligible articles prior to July 2021. Two reviewers independently performed publications screening and data extraction, and quantitative and qualitative analyses were conducted. Fourteen articles were identified that fulfill the inclusion criteria. Studies with different designs reported nine lncRNAs that were experimentally validated to act as ceRNA in AD in human-related studies, including BACE1-AS, SNHG1, RPPH1, NEAT1, LINC00094, SOX21-AS1, LINC00507, MAGI2-AS3, and LINC01311. The BACE1-AS/BACE1 was the most frequent ceRNA pair. Among miRNAs, miR-107 played a key role by regulating three different loops. Understanding the various aspects of this regulatory mechanism can help elucidate the unknown etiology of AD and provide new molecular targets for use in therapeutic and clinical applications.

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Section: Discussionmentioning

confidence: 99%

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review

Sabaie

Amirinejad

Asadi

et al. 2021

Front. Aging Neurosci.

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“…An alternative method of enhancing intranasal delivery to the brain termed minimally invasive nasal depot (MIND) involves introducing a biodegradable NBT-containing thermo-gelling polymer gel into a pocket between nasal mucosa and skull bone in the olfactory epithelium region of the nasal cavity ( Padmakumar et al, 2021 ). MIND delivery of AntagoNATs, PS ASOs designed to upregulate BDNF through inhibition of BDNF-AS, in a rat resulted in wide brain distribution of AntagoNAT, and induced significant and sustained upregulation of BDNF protein within the brain.…”

Section: Novel Clinical Administration Techniquesmentioning

confidence: 99%

“…Interfering with function of a BDNF NAT, a regulatory lncRNA in the BDNF locus, using ICV administration of ASOs (termed AntagoNATs), results in increased expression of biologically active BDNF protein in mouse brain and proliferation and differentiation of neurons in mouse neurosphere cultures ( Modarresi et al, 2012 , Natural Antisense Transcripts ). Treatment with BDNF AntagoNAT targeted against BDNF-AS delivered using MIND technique induced widely distributed upregulation of BDNF protein in rat brain ( Padmakumar et al, 2021 ).…”

Section: Nbts In Orphan Neurological Disordersmentioning

confidence: 99%

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Khorkova

Hsiao

Wahlestedt

2021

Front. Mol. Biosci.

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The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid–based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood–brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with “common” diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of “common” disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.

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“…For this reason, a new modality, BDNF delivery via minimally invasive nasal depot (MIND), appears to be a promising PTSD treatment (Szekeres et al, 2010). In addition, several TrkB receptor agonists have been tested in veterans with PTSD, including the small molecule, 7,8-dihydroxyflavone, that showed beneficial effects in many patients (Padmakumar et al, 2021). In addition, as lithium displays TrkB agonism, it was found helpful, especially for the PTSD patients with impulsivity and affective instability (Sanz-García et al, 2016).…”

Section: The Virus and Fibrinolytic Systemmentioning

confidence: 99%

PTSD as an Endothelial Disease: Insights From COVID-19

Sfera

Osorio

Rahman

et al. 2021

Front. Cell. Neurosci.

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Graphical Abstract 1Covid-19 triggers endothelial cell (EC) senescence and dysfunction, likely predisposing to PTSD by increasing microvascular permeability that enables the extravasation of stress molecules into the brain trauma-processing networks in amygdala, hippocampus and the medial prefrontal cortex. The virus upregulates host angiotensin II (ANG II) (via S1 antigen), usurps furin/plasmin (via S2 antigen), mitochondria (via ORF9b), and Sigma-1 receptors (Sig-1Rs) via NSP6. These structures, previously associated with PTSD, link the SARS-CoV-2 virus to increased susceptibility for stress related disorders. As ECs are major producers of brain derived neurotrophic factor (BDNF), a neurotrophin altered in PTSD, senescent ECs lower this molecule further, predisposing to stress related disorders.

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Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain

Cited by 42 publications

References 55 publications

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

PTSD as an Endothelial Disease: Insights From COVID-19

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