PMID- 35356682
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220401
IS  - 2162-2531 (Print)
IS  - 2162-2531 (Electronic)
IS  - 2162-2531 (Linking)
VI  - 28
DP  - 2022 Jun 14
TI  - Development of an mRNA replacement therapy for phenylketonuria.
PG  - 87-98
LID - 10.1016/j.omtn.2022.02.020 [doi]
AB  - Phenylketonuria (PKU) is an inborn error caused by deficiencies in phenylalanine 
      (Phe) metabolism. Mutations in the phenylalanine hydroxylase (PAH) gene are the 
      main cause of the disease whose signature hallmarks of toxically elevated levels 
      of Phe accumulation in plasma and organs such as the brain, result in 
      irreversible intellectual disability. Here, we present a unique approach to 
      treating PKU deficiency by using an mRNA replacement therapy. A full-length mRNA 
      encoding human PAH (hPAH) is encapsulated in our proprietary lipid nanoparticle 
      LUNAR and delivered to a Pah (enu2) mouse model that carries a missense mutation 
      in the mouse PAH gene. Animals carrying this missense mutation develop 
      hyperphenylalanemia and hypotyrosinemia in plasma, two clinical features commonly 
      observed in the clinical presentation of PKU. We show that intravenous infusion 
      of LUNAR-hPAH mRNA can generate high levels of hPAH protein in hepatocytes and 
      restore the Phe metabolism in the Pah (enu2) mouse model. Together, these data 
      establish a proof of principle of a novel mRNA replacement therapy to treat PKU.
CI  - (c) 2022 The Authors.
FAU - Perez-Garcia, Carlos G
AU  - Perez-Garcia CG
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Diaz-Trelles, Ramon
AU  - Diaz-Trelles R
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Vega, Jerel Boyd
AU  - Vega JB
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Bao, Yanjie
AU  - Bao Y
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Sablad, Marciano
AU  - Sablad M
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Limphong, Patty
AU  - Limphong P
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Chikamatsu, Simon
AU  - Chikamatsu S
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Yu, Hailong
AU  - Yu H
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Taylor, Wendy
AU  - Taylor W
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Karmali, Priya P
AU  - Karmali PP
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Tachikawa, Kiyoshi
AU  - Tachikawa K
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
FAU - Chivukula, Padmanabh
AU  - Chivukula P
AD  - Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 
      92121, USA.
LA  - eng
PT  - Journal Article
DEP - 20220228
PL  - United States
TA  - Mol Ther Nucleic Acids
JT  - Molecular therapy. Nucleic acids
JID - 101581621
PMC - PMC8933640
OTO - NOTNLM
OT  - LNP
OT  - MT: Delivery Strategies
OT  - PAH
OT  - PKU
OT  - hepatocytes
OT  - lipid nanoparticle
OT  - liver
OT  - mRNA
OT  - phenylketonuria
OT  - replacement
OT  - therapy
COIS- The work included in this manuscript was performed using funds provided by 
      Arcturus Therapeutics, Inc. The authors are current or former employees of 
      Arcturus Therapeutics Inc.
EDAT- 2022/04/01 06:00
MHDA- 2022/04/01 06:01
PMCR- 2022/02/28
CRDT- 2022/03/31 05:35
PHST- 2022/01/03 00:00 [received]
PHST- 2022/02/25 00:00 [accepted]
PHST- 2022/03/31 05:35 [entrez]
PHST- 2022/04/01 06:00 [pubmed]
PHST- 2022/04/01 06:01 [medline]
PHST- 2022/02/28 00:00 [pmc-release]
AID - S2162-2531(22)00048-8 [pii]
AID - 10.1016/j.omtn.2022.02.020 [doi]
PST - epublish
SO  - Mol Ther Nucleic Acids. 2022 Feb 28;28:87-98. doi: 10.1016/j.omtn.2022.02.020. 
      eCollection 2022 Jun 14.