Two Science issues new technology breaks the blood-brain barrier to enable efficient delivery of brain protein drugs

June 3, 2020/PRNewswire
BIOON / - The treatment of brain diseases has been slow, and one of the main obstacles is the blood-brain barrier, which greatly limits the effective transmission of therapeutic drugs to the central nervous systemThe development of various delivery vehicles will allow various drugs to pass through BBB into the brain lesions to achieve efficacy is a research hotspot for the treatment of neurological diseases, this field has made a breakthrough recentlyon May 27,, researchers from Denali Therapeutics Incand Vanderbilt University published two consecutive research papers in the journal Science Translational Medicine, using a TransportCarrier(TV) based on Fc fragments to successfully deliver macromolecule protein drugs to the brains of mice and monkeys and to treat the diseasethe first study, entitled "Brain delivery and activity of a lysomal enzyme using a blood-brain barrier, "car in mice", was carried out by Denali Therapeutics Incand researchers at Vanderbilt UniversityMost lysosomal storage diseases (lysosomal storage diseases, LSDs) involve the damage to the performing central nervous system (CNS) caused by the lack of lysoasesThe treatment of neuropathic LSDs remains a considerable challenge, as approved intravenous enzyme therapy is ineffective in altering central nervous system diseases because they do not effectively cross the blood-brain barrier (blood-brain barrier, BBB)Picture Source:Science Translational Medicineresearchers describe a treatment platform for enzyme-substitution therapies that increase brain exposure to drugs Enzyme transport vector (enzyme transport transport, ETV) is a lysosome enzyme that fuses into the Fc domain, which has been designed to bind to transferrin receptors to facilitate receptor-mediated trans-blood-brain barrier transport The researchers demonstrated in the models of cells and mice with defects in the aduinate 2-sulphatease (iduronate 2-sulfatase, IDS) that both the ETV fusion (ETV:IDS) containing IDS-- the lysosome enzyme senamein in type II viscose polysaccharides -- showed high intrinsic activity and the ability to degrade accumulated substrates The researchers found that ETV significantly improved brain transfer of IDS in preclinical models of the disease, enhancing the distribution of drugs throughout the brain in neurons, astrocytes and small glial cells Improvements in brain exposure to ETV: IDS translate into a reduction in the accumulation of substrates in these CNS cell types and surrounding tissues, and lead to the complete correction of the pathology associated with downstream diseases in the brain, including secondary accumulation of lysosome lipids, gene expression disturbances, nerve inflammation, and nerve axon damage These data highlight the therapeutic potential of The ETV platform for LSDs and provide preclinical proof of concept for the wider treatment of central nervous system diseases in TV therapy the second study, entitled "Brain delivery of the spade of the spade proteins using an Fc fragment blood-brain edre transport car in mice and monkeys", was independently produced by Denali Spas Inc In the paper, the researchers describe the development of a BBB transport vehicle (TV), which includes an engineered Fc fragment that uses receptor-mediated extracellular transport to deliver CNS biotherapeutic drugs by combining highly expressive endothelial cells Picture Source: Science Translational Medicine researchers used directional evolutionary techniques (without amino acid insertion, deletion, or non-natural appendages) to obtain TVs that could be combined to the top region of the human transferrin receptor (hTfR) The crystal structure of the TV-tfr complex shows that the TV binding site is far away from the transferrin and FcRn binding sites, which are further confirmed in vitro and in vivo Recombinant lying on fabs of the fusion anti-beta-secretion enzyme (BACE1) synthesizes antibody transport (ATV) molecules with the structure and stability of natural immunoglobulin G (IgG) The researchers found that intravenous injections of anti-BACE1 ATVs in hTfR-engineered mice and crab-eating monkeys significantly improved the intake of the central nervous system and maintained a pharmacological response These results suggest that the TV platform can easily accommodate many additional configurations, including bispecific antibody and protein fusion, resulting in a highly modular central nervous system transmission platform (BioValleyBioon.com) References: 1
Brain Delivery and activity of a lysomal enzyme using a blood-brain edbor sat transport in mice
Science Translational Medicine 27 May 2020: Vol 12, Issue 545, eay1163 DOI: 10.1126/scitranslmed.aay1163 2, Brain of The Marketing of proteins using an Fc blood-brained transport car in in the monkeys Science Medicine Medicine 27 May 2020: Vol 12, Issue 545, eay1359 DOI: 10.1126/scitranslmed.aay1359 3.