An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery
Abstract 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 humanTFRCknock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliverGBA1, 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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 27. Dez. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Huang, Qin [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2023.12.20.572615 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI041964977 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI041964977 | ||
| 003 | DE-627 | ||
| 005 | 20231228090640.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231223s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.12.20.572615 |2 doi | |
| 035 | |a (DE-627)XBI041964977 | ||
| 035 | |a (biorXiv)10.1101/2023.12.20.572615 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Huang, Qin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract 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 humanTFRCknock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliverGBA1, 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. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Chan, Ken Y. |4 aut | |
| 700 | 1 | |a Lou, Shan |4 aut | |
| 700 | 1 | |a Keyes, Casey |4 aut | |
| 700 | 1 | |a Wu, Jason |4 aut | |
| 700 | 1 | |a Botticello-Romero, Nuria R |4 aut | |
| 700 | 1 | |a Zheng, Qingxia |4 aut | |
| 700 | 1 | |a Johnston, Jencilin |4 aut | |
| 700 | 1 | |a Mills, Allan |4 aut | |
| 700 | 1 | |a Brauer, Pamela P. |4 aut | |
| 700 | 1 | |a Clouse, Gabrielle |4 aut | |
| 700 | 1 | |a Pacouret, Simon |4 aut | |
| 700 | 1 | |a Harvey, John W. |4 aut | |
| 700 | 1 | |a Beddow, Thomas |4 aut | |
| 700 | 1 | |a Hurley, Jenna K. |4 aut | |
| 700 | 1 | |a Tobey, Isabelle G. |0 (orcid)0000-0001-5428-3809 |4 aut | |
| 700 | 1 | |a Powell, Megan |4 aut | |
| 700 | 1 | |a Chen, Albert T. |0 (orcid)0000-0002-5387-0208 |4 aut | |
| 700 | 1 | |a Barry, Andrew J. |0 (orcid)0000-0002-4667-679X |4 aut | |
| 700 | 1 | |a Eid, Fatma-Elzahraa |0 (orcid)0000-0002-6822-9536 |4 aut | |
| 700 | 1 | |a Chan, Yujia A. |0 (orcid)0000-0002-0731-637X |4 aut | |
| 700 | 1 | |a Deverman, Benjamin E. |0 (orcid)0000-0002-6223-9303 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 27. Dez. |
| 773 | 1 | 8 | |g year:2023 |g day:27 |g month:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.12.20.572615 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 27 |c 12 | ||