PMID- 21222531
OWN - NLM
STAT- MEDLINE
DCOM- 20110822
LR  - 20161125
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Linking)
VI  - 22
IP  - 5
DP  - 2011 May
TI  - Mycophenolate mofetil impairs transduction of single-stranded adeno-associated 
      viral vectors.
PG  - 605-12
LID - 10.1089/hum.2010.222 [doi]
AB  - Adeno-associated virus (AAV) liver-directed gene therapy seems a feasible 
      treatment for Crigler-Najjar syndrome type I, an inherited liver disorder 
      characterized by severe unconjugated hyperbilirubinemia. Transient 
      immunosuppression coupled with vector administration seems needed to overcome 
      host immune responses that prevent long-term expression in patients. The 
      immunosuppressive mycophenolate mofetil (MMF), which inhibits de novo synthesis 
      of purines, is a promising candidate. To investigate the potential use of MMF in 
      patients with Crigler-Najjar syndrome, we studied its effect on single-stranded 
      AAV (ssAAV)-mediated correction of hyperbilirubinemia in the relevant preclinical 
      model, the Gunn rat. Although MMF was well tolerated and effective it also 
      impaired the efficacy of ssAAV. Subsequent in vitro studies showed that this 
      effect is not specific for UGT1A deficiency. In fact, clinical relevant 
      concentrations of mycophenolic acid (MPA), the active compound of MMF, also 
      impair the transduction of HEK-293T cells by ssAAV. Because this effect was 
      reversed by guanosine addition, it seems that intracellular levels of this 
      nucleotide become limited, suggesting that MPA impairs second-strand DNA 
      synthesis. This is corroborated by observations that MPA did not impair 
      transduction of 293T cells by a self-complementary AAV (scAAV) vector and that 
      MMF did not reduce the scAAV efficacy in the Gunn rat. In conclusion, MMF impairs 
      ssAAV-mediated liver-directed gene therapy, which is relevant for the use of this 
      immunosuppressive agent with single-stranded vectors. Furthermore, because this 
      effect is due to impaired second-strand synthesis, the use of MMF with scAAV 
      seems warranted.
FAU - Montenegro-Miranda, Paula S
AU  - Montenegro-Miranda PS
AD  - Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, 1105 
      BK Amsterdam, The Netherlands.
FAU - ten Bloemendaal, Lysbeth
AU  - ten Bloemendaal L
FAU - Kunne, Cindy
AU  - Kunne C
FAU - de Waart, Dirk R
AU  - de Waart DR
FAU - Bosma, Piter J
AU  - Bosma PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110411
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (DNA Primers)
RN  - 0 (Immunosuppressive Agents)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - RFM9X3LJ49 (Bilirubin)
SB  - IM
MH  - Animals
MH  - Bilirubin/blood
MH  - Cell Line
MH  - Crigler-Najjar Syndrome/genetics/immunology/therapy
MH  - DNA Primers/genetics
MH  - DNA Replication/drug effects
MH  - Dependovirus/*drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/drug effects/*genetics
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Linear Models
MH  - Mycophenolic Acid/*analogs & derivatives/pharmacology
MH  - Polymerase Chain Reaction
MH  - Rats
MH  - Rats, Gunn
MH  - Transduction, Genetic/*methods
EDAT- 2011/01/13 06:00
MHDA- 2011/08/23 06:00
CRDT- 2011/01/13 06:00
PHST- 2011/01/13 06:00 [entrez]
PHST- 2011/01/13 06:00 [pubmed]
PHST- 2011/08/23 06:00 [medline]
AID - 10.1089/hum.2010.222 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2011 May;22(5):605-12. doi: 10.1089/hum.2010.222. Epub 2011 Apr 
      11.