AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model.
Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+  binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported. In this study, the nanobodies have been combined into a single bispecific format able to simultaneously shield mutant plasma gelsolin from intracellular furin and extracellular MT1-MMP activity. We report the successful in vivo expression of this bispecific nanobody following adeno-associated virus serotype 9 gene therapy in gelsolin amyloidosis mice. Using SPECT/CT and immunohistochemistry, a reduction in gelsolin amyloid burden was detected which translated into improved muscle contractile properties. We conclude that a nanobody-based gene therapy using adeno-associated viruses shows great potential as a novel strategy in gelsolin amyloidosis and potentially other amyloid diseases.
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Adriaan
A
Verhelle
Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium.
Nisha
N
Nair
Department of Movement and Sport Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Inge
I
Everaert
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Wouter
W
Van Overbeke
Department of Medical and Forensic Pathology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Lynn
L
Supply
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Olivier
O
Zwaenepoel
In Vivo Cellular and Molecular Imaging Laboratory, Free University of Brussels (VUB), Brussels, Belgium.
Cindy
C
Peleman
Department of Medical and Forensic Pathology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Jo
J
Van Dorpe
In Vivo Cellular and Molecular Imaging Laboratory, Free University of Brussels (VUB), Brussels, Belgium.
Tony
T
Lahoutte
In Vivo Cellular and Molecular Imaging Laboratory, Free University of Brussels (VUB), Brussels, Belgium.
Nick
N
Devoogdt
Department of Movement and Sport Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Wim
W
Derave
Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium.|Department of Cardiovascular Sciences, Catholic University of Leuven (KU Leuven), Leuven, Belgium.
Marinee K
MK
Chuah
Department of Gene Therapy & Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium.|Department of Cardiovascular Sciences, Catholic University of Leuven (KU Leuven), Leuven, Belgium.
Thierry
T
VandenDriessche
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Jan
J
Gettemans
D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D045683:Furin / Q000276:immunology / Q000627:therapeutic use; D018260:Gelsolin / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D017354:Point Mutation / Q000235:genetics; D061905:Single-Domain Antibodies / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D018033:Antibodies, Bispecific; D018260:Gelsolin; D061905:Single-Domain Antibodies; D045683:Furin; D053511:Matrix Metalloproteinase 14