PMID- 26125662
OWN - NLM
STAT- MEDLINE
DCOM- 20160620
LR  - 20150918
IS  - 2159-3345 (Electronic)
IS  - 2159-3337 (Linking)
VI  - 25
IP  - 5
DP  - 2015 Oct
TI  - In Vitro Evaluation of a Novel mRNA-Based Therapeutic Strategy for the Treatment 
      of Patients Suffering from Alpha-1-Antitrypsin Deficiency.
PG  - 235-44
LID - 10.1089/nat.2015.0537 [doi]
AB  - In single-gene disorders, like alpha-1-antitrypsin deficiency (AATD), a gene 
      mutation causes missing or dysfunctional protein synthesis. This, in turn, can 
      lead to serious complications for the patient affected. Furthermore, single-gene 
      disorders are associated with severe early-onset conditions and necessitate 
      expensive lifelong care. Until nowadays, therapeutic treatment options are still 
      limited, cost-intensive, or lack effectiveness. For these reasons, we aim to 
      develop a novel mRNA-based therapeutic strategy for the treatment of single-gene 
      disorders, such as AATD, which is based on the induction of de novo synthesis of 
      the functional proteins. Therefore, an alpha-1-antitrypsin (AAT) encoding mRNA 
      was generated by in vitro transcription. After in vitro delivery of the mRNA to 
      different cells, protein expression and functionality, as well as adverse effects 
      and mRNA serum stability, were analyzed. Our results show that the AAT 
      mRNA-transfected cells express the AAT protein in high amounts within the first 
      24 h. Moreover, the expressed AAT protein is highly functional, since the 
      activity of elastase is significantly inhibited. Our data also show that mRNA 
      concentrations up to 1 mug per 150,000 cells have no adverse effects on cell 
      viability and immune activation. Furthermore, the encapsulated AAT encoding mRNA 
      is stable and functional in human serum for up to 30 min. Overall, the proposed 
      project provides an innovative, highly promising, and safe therapeutic approach 
      and, thus, promises a novel progress in the treatment of single-gene disorders, 
      whereby affected patients could greatly benefit.
FAU - Michel, Tatjana
AU  - Michel T
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Kankura, Anna
AU  - Kankura A
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Salinas Medina, Martha L
AU  - Salinas Medina ML
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Kurz, Julia
AU  - Kurz J
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Behring, Andreas
AU  - Behring A
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Avci-Adali, Meltem
AU  - Avci-Adali M
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Nolte, Andrea
AU  - Nolte A
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Schlensak, Christian
AU  - Schlensak C
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Wendel, Hans Peter
AU  - Wendel HP
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
FAU - Krajewski, Stefanie
AU  - Krajewski S
AD  - Clinical Research Laboratory, Department of Thoracic and Cardiovascular Surgery, 
      University Hospital Tuebingen, Tuebingen University , Tuebingen, Germany .
LA  - eng
PT  - Journal Article
DEP - 20150630
PL  - United States
TA  - Nucleic Acid Ther
JT  - Nucleic acid therapeutics
JID - 101562758
RN  - 0 (Cytokines)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Cytokines/biosynthesis
MH  - Genetic Therapy
MH  - HEK293 Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - Protein Biosynthesis
MH  - RNA Stability
MH  - RNA, Messenger/biosynthesis/*genetics
MH  - Transcription, Genetic
MH  - Transfection
MH  - alpha 1-Antitrypsin Deficiency/*therapy
EDAT- 2015/07/01 06:00
MHDA- 2016/06/21 06:00
CRDT- 2015/07/01 06:00
PHST- 2015/07/01 06:00 [entrez]
PHST- 2015/07/01 06:00 [pubmed]
PHST- 2016/06/21 06:00 [medline]
AID - 10.1089/nat.2015.0537 [doi]
PST - ppublish
SO  - Nucleic Acid Ther. 2015 Oct;25(5):235-44. doi: 10.1089/nat.2015.0537. Epub 2015 
      Jun 30.