Systemic messenger RNA as an etiological treatment for acute intermittent porphyria

被引：145

作者：

Jiang, Lei ^{[1
]}

Berraondo, Pedro ^{[2
,3
,4
]}

Jerico, Daniel ^{[3
,5
]}

Guey, Lin T. ^{[1
]}

Sampedro, Ana ^{[3
,5
]}

Frassetto, Andrea ^{[1
]}

Benenato, Kerry E. ^{[1
]}

Burke, Kristine ^{[1
]}

Santamaria, Eva ^{[3
,5
,6
]}

Alegre, Manuel ^{[7
,8
]}

Pejenaute, Alvaro ^{[9
]}

Kalariya, Mayur ^{[1
]}

Butcher, William ^{[1
]}

Park, Ji-Sun ^{[1
]}

Zhu, Xuling ^{[1
]}

Sabnis, Staci ^{[1
]}

Kumarasinghe, E. Sathyajith ^{[1
]}

Salerno, Timothy ^{[1
]}

Kenney, Matthew ^{[1
]}

Lukacs, Christine M. ^{[1
]}

Avila, Matias A. ^{[3
,5
,6
]}

Martini, Paolo G. V. ^{[1
]}

Fontanellas, Antonio ^{[3
,5
,6
]}

机构：

[1] Moderna Therapeut, Cambridge, MA 02139 USA

[2] Univ Navarra, Program Immunol & Immunotherapy, Ctr Appl Med Res CIMA, Pamplona, Spain

[3] Inst Invest Sanitaria Navarra IdiSNA, Pamplona, Spain

[4] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[5] Univ Navarra, Hepatol Program, Ctr Appl Med Res CIMA, Pamplona, Spain

[6] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain

[7] Univ Navarra, Dept Clin Neurophysiol, Clin Univ, Pamplona, Spain

[8] Univ Navarra, Neurosci Program, Ctr Appl Med Res CIMA, Neurophysiol Lab, Pamplona, Spain

[9] Univ Navarra, Dept Biochem & Genet, Pamplona, Spain

来源：

NATURE MEDICINE | 2018年 / 24卷 / 12期

关键词：

HEME-ARGINATE; PORPHOBILINOGEN DEAMINASE; AMINOLEVULINIC-ACID; MITOCHONDRIAL; DEFICIENCY; THERAPY; METABOLISM; EXPRESSION; NEUROPATHY; ATTACKS;

D O I：

10.1038/s41591-018-0199-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.

引用

页码：1899 / +

页数：13

共 46 条

[1] Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia [J].