Development of an mRNA replacement therapy for phenylketonuria
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...
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| Published in | Molecular therapy. Nucleic acids Vol. 28; pp. 87 - 98 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
14.06.2022
American Society of Gene & Cell Therapy Elsevier |
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| Online Access | Get full text |
| ISSN | 2162-2531 2162-2531 |
| DOI | 10.1016/j.omtn.2022.02.020 |
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| Abstract | 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 Pahenu2 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 Pahenu2 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU.
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Perez-Garcia-Trelles and colleagues have developed an mRNA replacement therapeutic approach to treat the underlying cause of phenylketonuria in patients carrying a phenylalanine hydroxylase mutation. |
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| AbstractList | 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.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. 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 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 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU. 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 Pahenu2 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 Pahenu2 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU. 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. Perez-Garcia-Trelles and colleagues have developed an mRNA replacement therapeutic approach to treat the underlying cause of phenylketonuria in patients carrying a phenylalanine hydroxylase mutation. 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 Pahenu2 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 Pahenu2 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU. [Display omitted] Perez-Garcia-Trelles and colleagues have developed an mRNA replacement therapeutic approach to treat the underlying cause of phenylketonuria in patients carrying a phenylalanine hydroxylase mutation. |
| Author | Yu, Hailong Vega, Jerel Boyd Chikamatsu, Simon Taylor, Wendy Limphong, Patty Karmali, Priya P. Chivukula, Padmanabh Perez-Garcia, Carlos G. Tachikawa, Kiyoshi Diaz-Trelles, Ramon Bao, Yanjie Sablad, Marciano |
| Author_xml | – sequence: 1 givenname: Carlos G. surname: Perez-Garcia fullname: Perez-Garcia, Carlos G. email: carlos@arcturusrx.com organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 2 givenname: Ramon orcidid: 0000-0002-2666-9728 surname: Diaz-Trelles fullname: Diaz-Trelles, Ramon organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 3 givenname: Jerel Boyd orcidid: 0000-0003-0998-4715 surname: Vega fullname: Vega, Jerel Boyd organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 4 givenname: Yanjie surname: Bao fullname: Bao, Yanjie organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 5 givenname: Marciano surname: Sablad fullname: Sablad, Marciano organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 6 givenname: Patty surname: Limphong fullname: Limphong, Patty organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 7 givenname: Simon orcidid: 0000-0002-3165-4424 surname: Chikamatsu fullname: Chikamatsu, Simon organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 8 givenname: Hailong surname: Yu fullname: Yu, Hailong organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 9 givenname: Wendy surname: Taylor fullname: Taylor, Wendy organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 10 givenname: Priya P. surname: Karmali fullname: Karmali, Priya P. organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 11 givenname: Kiyoshi surname: Tachikawa fullname: Tachikawa, Kiyoshi organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA – sequence: 12 givenname: Padmanabh surname: Chivukula fullname: Chivukula, Padmanabh organization: Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA 92121, USA |
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| Keywords | lipid nanoparticle liver therapy PAH mRNA PKU MT: Delivery Strategies phenylketonuria replacement hepatocytes LNP |
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| Title | Development of an mRNA replacement therapy for phenylketonuria |
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