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1.
Science ; 384(6701): 1220-1227, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38753766

RESUMO

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of human TFRC knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.


Assuntos
Antígenos CD , Encéfalo , Capsídeo , Técnicas de Transferência de Genes , Vetores Genéticos , Glucosilceramidase , Receptores da Transferrina , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos CD/genética , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Dependovirus , Células Endoteliais/metabolismo , Técnicas de Introdução de Genes , Terapia Genética , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Glucosilceramidase/genética , Doença de Gaucher/genética , Doença de Gaucher/terapia , Doença de Parkinson/genética , Doença de Parkinson/terapia
2.
bioRxiv ; 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38187643

RESUMO

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.

3.
Int J Nanomedicine ; 11: 45-52, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26730189

RESUMO

Vibrational spectroscopy is a powerful analytical tool that assesses molecular properties based on spectroscopic signatures. In this study, the effect of gold nanoparticle morphology (spherical vs multi-branched) was assessed for the characterization of a Raman signal (ie, molecular fingerprint) that may be helpful for numerous medical applications. Multi-branched gold nanoparticles (MBAuNPs) were fabricated using a green chemistry method which employed the reduction of gold ion solute by 2-[4-(2-hydroxyethyl)-1-piperazyl] ethane sulfonic acid. Two types of reporter dyes, indocyanine (IR820 and IR792) and carbocyanine (DTTC [3,3'-diethylthiatricarbocyanine iodide] and DTDC [3,3'-diethylthiadicarbocyanine iodide]), were functionalized to the surface of the MBAuNPs and stabilized with denatured bovine serum albumin, thus forming the surface-enhanced Raman spectroscopy tag. Fluorescein isothiocyanate-conjugated anti-epidermal growth factor receptor to the surface-enhanced Raman spectroscopy tags and the properties of the resulting conjugates were assessed through determination of the Raman signal. Using the MBAuNP Raman probes synthesized in this manner, we demonstrated that MBAuNP provided significantly more surface-enhanced Raman scattering signal when compared with the associated spherical gold nanoparticle of similar size and concentration. MBAuNP enhancements were retained in the surface-enhanced Raman spectroscopy tags complexed to anti-epidermal growth factor receptor, providing evidence that this could be a useful biological probe for enhanced Raman molecular fingerprinting. Furthermore, while utilizing IR820 as a novel reporter dye linked with MBAuNP, superior Raman signal fingerprint results were obtained. Such results provide significant promise for the use of MBAuNP in the detection of numerous diseases for which biologically specific surface markers exist.


Assuntos
Ouro/química , Nanopartículas/química , Análise Espectral Raman/métodos , Anticorpos/química , Benzotiazóis , Carbocianinas , Receptores ErbB/imunologia , Fluoresceína-5-Isotiocianato/química , Química Verde , Verde de Indocianina/análogos & derivados , Verde de Indocianina/análise , Verde de Indocianina/química , Técnicas de Diagnóstico Molecular/instrumentação , Técnicas de Diagnóstico Molecular/métodos , Sondas Moleculares/análise , Sondas Moleculares/química , Soroalbumina Bovina/química , Análise Espectral Raman/instrumentação
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