Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression.
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
Christian
C
Mueller
Jeffrey D
JD
Chulay
Bruce C
BC
Trapnell
Margaret
M
Humphries
Brenna
B
Carey
Robert A
RA
Sandhaus
Noel G
NG
McElvaney
Louis
L
Messina
Qiushi
Q
Tang
Farshid N
FN
Rouhani
Martha
M
Campbell-Thompson
Ann Dongtao
AD
Fu
Anthony
A
Yachnis
David R
DR
Knop
Guo-Jie
GJ
Ye
Mark
M
Brantly
Roberto
R
Calcedo
Suryanarayan
S
Somanathan
Lee P
LP
Richman
Robert H
RH
Vonderheide
Maigan A
MA
Hulme
Todd M
TM
Brusko
James M
JM
Wilson
Terence R
TR
Flotte
D001706:Biopsy; D002213:Capsid / Q000276:immunology; D002999:Clone Cells / Q000737:chemistry; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D007273:Injections, Intramuscular; D008213:Lymphocyte Activation; D018482:Muscle, Skeletal / Q000737:chemistry / Q000276:immunology / Q000473:pathology / Q000821:virology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019076:Transgenes / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019896:alpha 1-Antitrypsin Deficiency / Q000628:therapy*
D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin