Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species

被引：253

作者：

Tabebordbar, Mohammadsharif ^{[1
]}

Lagerborg, Kim A. ^{[1
,2
]}

Stanton, Alexandra ^{[1
,3
]}

King, Emily M. ^{[1
]}

Ye, Simon ^{[1
,4
]}

Tellez, Liana ^{[1
]}

Krunnfusz, Allison ^{[1
]}

Tavakoli, Sahar ^{[5
,6
,7
,8
,9
]}

Widrick, Jeffrey J. ^{[10
]}

Messemer, Kathleen A. ^{[5
,6
,7
]}

Troiano, Emily C. ^{[10
]}

Moghadaszadeh, Behzad ^{[10
]}

Peacker, Bryan L. ^{[5
,6
,7
]}

Leacock, Krystynne A. ^{[5
,6
,7
]}

Horwitz, Naftali ^{[5
,6
,7
,12
]}

Beggs, Alan H. ^{[1
,10
]}

Wagers, Amy J. ^{[5
,6
,7
,12
]}

Sabeti, Pardis C. ^{[1
,11
,13
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Harvard Program Biol & Biomed Sci, Boston, MA 02115 USA

[3] Harvard Med Sch, Harvard Program Virol, Boston, MA 02115 USA

[4] MIT, Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA

[5] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[6] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[7] Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Boston, MA 02115 USA

[8] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[9] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[10] Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA

[11] Harvard Univ, FAS Ctr Syst Biol, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA

[12] Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA

[13] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2021年 / 184卷 / 19期

关键词：

ADENOASSOCIATED VIRUS; MODEL; SELECTION; SKELETAL; VECTORS; STEM; IDENTIFICATION; FIBRONECTIN; EXPRESSION; EFFICIENT;

D O I：

10.1016/j.cell.2021.08.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.

引用

页码：4919 / +

页数：42

共 50 条

[1] Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species
Tabebordbar, S.
Lagerborg, K.
Ye, S.
Stanton, A.
King, E.
Tellez, L.
Krunnfusz, A.
Tavakoli, S.
Widrick, J.
Messemer, K.
Troiano, E.
Moghadaszadeh, B.
Peacker, B.
Leacock, K.
Horwitz, N.
Beggs, A.
Wagers, A.
Sabeti, P.
NEUROMUSCULAR DISORDERS, 2022, 32 : S96 - S96
[2] Novel AAV capsid variant for muscle-directed gene therapy
Lemoine, J.
Just, S.
Dominguez, N.
Galy, A.
Buening, N.
Richard, I.
HUMAN GENE THERAPY, 2021, 32 (19-20) : A29 - A29
[3] Directed Evolution of Adeno-Associated Virus Variants Enabling Potent Gene Delivery for the Treatment of Osteoarthritis
Kim, Y. J.
Ji, E. H.
Joo, K. I.
HUMAN GENE THERAPY, 2024, 35 (3-4) : A106 - A106
[4] Directed evolution of AAV2 yields novel capsid variants
Maheshri, N
Kaspar, B
Schaffer, DV
MOLECULAR THERAPY, 2004, 9 : S8 - S8
[5] MyoScreen™, a discovery platform for candidate selection of muscle-directed AAV gene therapies
Votteler, J.
Le Guiner, C.
Webb, S.
Young, J.
Duchemin-Pelletier, E.
Lorintiu, O.
Bourdon, A.
Hammond, S.
Tretiakova, A.
Samulski, R. J.
HUMAN GENE THERAPY, 2024, 35 (3-4) : A254 - A255
[6] Antibody Conjugated AAV Vectors for Efficient and Specific Skeletal Muscle Directed Gene Delivery across Species
Samai, Poulami
Stec, Michael
Le Rouzic, Valerie
Khan, Naveen
Golann, David
Jose, Clarisse Lou
Cherravuru, Samvitha
Tareen, Ammar
Sleeman, Mark
Moller-Tank, Sven H.
Kyratsous, Christos
Sabin, Leah
MOLECULAR THERAPY, 2023, 31 (04) : 22 - 23
[7] Capsid-Modified Adenoviral Vectors for Improved Muscle-Directed Gene Therapy
Guse, Kilian
Suzuki, Masataka
Sule, Gautam
Bertin, Terry K.
Tyynismaa, Henna
Ahola-Erkkila, Sofia
Palmer, Donna
Suomalainen, Anu
Ng, Philip
Cerullo, Vincenzo
Hemminki, Akseli
Lee, Brendan
HUMAN GENE THERAPY, 2012, 23 (10) : 1065 - 1070
[8] NGS and Bioinformatics Pipeline for Targeted AAV Delivery by Directed Capsid Evolution
Marsic, Damien
Boye, Sanford L.
Boye, Shannon E.
Zolotukhin, Sergei
MOLECULAR THERAPY, 2017, 25 (05) : 260 - 260
[9] Muscle-directed gene therapy for phenylketonuria with self-complementary AAV vectors
Kume, A.
Yagi, H.
Mizukami, H.
Urabe, M.
Tsukahara, T.
Uchibori, R.
Ozawa, K.
HUMAN GENE THERAPY, 2011, 22 (10) : A49 - A50
[10] Directed evolution of AAV mutants for enhanced gene delivery
Schaffer, DV
Maheshri, N
PROCEEDINGS OF THE 26TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-7, 2004, 26 : 3520 - 3523

← 1 2 3 4 5 →