scholarly journals A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke

2021 ◽  
Vol 8 ◽  
Author(s):  
Brett A. Eyford ◽  
Chaahat S. B. Singh ◽  
Thomas Abraham ◽  
Lonna Munro ◽  
Kyung Bok Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Central Nervous System ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Disease Model ◽  
Brain Barrier ◽  
Blood Brain ◽  
Peptide Carrier ◽  
The Central Nervous System

The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of neuroinflammation (NI) of the central nervous system. A twelve-amino acid peptide that transcytoses the BBB, termed MTfp, was chemically conjugated to siRNA to create a novel peptide-oligonucleotide conjugate (POC), directed to downregulate NOX4, a gene thought responsible for oxidative stress in ischemic stroke. The MTfp-NOX4 POC has the ability to cross the intact BBB and knockdown NOX4 expression in the brain. Following induction of ischemic stroke, animals pretreated with the POC exhibited significantly smaller infarcts; accompanied by increased protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp can act as a nanomule to facilitate BBB transcytosis of siRNAs; where the NOX-4 specific siRNA moiety can elicit effective therapeutic knockdown of a gene responsible for oxidative stress in the central nervous system. This study is the first to conclusively demonstrate both siRNA-carrier delivery and therapeutic efficacy in any CNS disease model where the BBB remains intact and thus offers new avenues for potential treatments of oxidative stress underlying neuroinflammation in a variety of neuropathologies that are currently refractory to existing therapies.

scholarly journals A Nanomule Peptide-siRNA Conjugate that Traverses the Intact Blood Brain Barrier and Attenuates Stroke

2019 ◽  
Author(s):  
Brett A. Eyford ◽  
Chaahat S.B. Singh ◽  
Thomas Abraham ◽  
Lonna Munro ◽  
Kyung Bok Choi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Significant Protection ◽  
Amino Acid Peptide ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

AbstractThe blood-brain barrier (BBB), hinders the distribution of therapeutics, intended for treatment of diseases of the brain. A twelve-amino acid peptide, termed MTfp, was derived from MTf, and retains the ability to cross the BBB intact and ferry cargo into intacellular organelles within neurons, glia and microglia in the brain. A novel MTfp-siRNA peptide-oligonucleotide conjugate (POC), directed against NOX4, a gene known to potentiate ischemic stroke, was chemically synthesized. The MTfp-NOX4 siRNA POC traversed the BBB, resulting in the knockdown of NOX4 expression in the brain. Following induction of ischemic stroke, animals treated with the POC exhibited significantly smaller infarcts; accompanied by significant protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp portion, of this novel POC, can facilitate BBB transcytosis; where the siRNA moiety can elicit effective therapeutic knockdown of a gene associated with a disease of the central nervous system (CNS). This is a general platform to transport therapeutics to the CNS and thereby, offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.

scholarly journals Permeability of the Blood-Brain Barrier and Transport of Nanobodies Across the Blood-Brain Barrier

2018 ◽  
Vol 62 (1) ◽  
pp. 59-66 ◽  
Author(s):  
I. Širochmanová ◽  
Ľ. Čomor ◽  
E. Káňová ◽  
I. Jiménez-Munguía ◽  
Z. Tkáčová ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Chemical Properties ◽  
Cost Effective ◽  
Central Nervous System Disease ◽  
Brain Barrier ◽  
Promising Alternative ◽  
Blood Brain ◽  
The Central Nervous System

Abstract The presence of a blood-brain barrier (BBB) and a blood-cerebrospinal fluid barrier presents animmense challenge for effective delivery of therapeutics to the central nervous system. Many potential drugs, which are effective at their site of action, have failed due to the lack of distribution in sufficient quantity to the central nervous system (CNS). In consequence, many diseases of the central nervous system remain undertreated. Antibodies, IgG for example, are difficult to deliver to the CNS due to their size (~155 kDa), physico-chemical properties and the presence of Fc receptor on the blood-brain barrier. Smaller antibodies, like the recently developed nanobodies, may overcome the obstacle of the BBB and enter into the CNS. The nanobodies are the smallest available antigen-binding fragments harbouring the full antigenbinding capacity of conventional antibodies. They represent a new generation of therapeutics with exceptional properties, such as: recognition of unique epitopes, target specificity, high affinity, high solubility, high stability and high expression yields in cost-effective recombinant production. Their ability to permeate across the BBBmakes thema promising alternative for central nervous system disease therapeutics. In this review, we have systematically presented different aspects of the BBB, drug delivery mechanisms employed to cross the BBB, and finally nanobodies — a potential therapeutic molecule against neuroinfections.

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