ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model

Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alka...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Owen Daly [verfasserIn] Azita Josefine Mahiny [verfasserIn] Sara Majeski [verfasserIn] Kevin McClintock [verfasserIn] Julia Reichert [verfasserIn] Gábor Boros [verfasserIn] Gábor Tamás Szabó [verfasserIn] Jonas Reinholz [verfasserIn] Petra Schreiner [verfasserIn] Steve Reid [verfasserIn] Kieu Lam [verfasserIn] Marlen Lepper [verfasserIn] Melanie Adler [verfasserIn] Tracy Meffen [verfasserIn] James Heyes [verfasserIn] Katalin Karikó [verfasserIn] Pete Lutwyche [verfasserIn] Irena Vlatkovic [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD)

Übergeordnetes Werk:	In: Biomedicines - MDPI AG, 2014, 11(2023), 6, p 1735
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:6, p 1735

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/biomedicines11061735

Katalog-ID:	DOAJ094202230

Internformat


LEADER	01000naa a22002652 4500
001	DOAJ094202230
003	DE-627
005	20240413031227.0
007	cr uuu---uuuuu
008	240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.3390/biomedicines11061735 \|2 doi
035			\|a (DE-627)DOAJ094202230
035			\|a (DE-599)DOAJ25fe821524ea47a48910c484bef99572
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
050		0	\|a QH301-705.5
100	0		\|a Owen Daly \|e verfasserin \|4 aut
245	1	0	\|a ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
264		1	\|c 2023
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
650		4	\|a lipid nanoparticle-mRNA (LNP-mRNA)
650		4	\|a mRNA optimization
650		4	\|a mRNA therapeutic
650		4	\|a rare disease
650		4	\|a argininosuccinic aciduria (ASA)
650		4	\|a argininosuccinate lyase deficiency (ASLD)
653		0	\|a Biology (General)
700	0		\|a Azita Josefine Mahiny \|e verfasserin \|4 aut
700	0		\|a Sara Majeski \|e verfasserin \|4 aut
700	0		\|a Kevin McClintock \|e verfasserin \|4 aut
700	0		\|a Julia Reichert \|e verfasserin \|4 aut
700	0		\|a Gábor Boros \|e verfasserin \|4 aut
700	0		\|a Gábor Tamás Szabó \|e verfasserin \|4 aut
700	0		\|a Jonas Reinholz \|e verfasserin \|4 aut
700	0		\|a Petra Schreiner \|e verfasserin \|4 aut
700	0		\|a Steve Reid \|e verfasserin \|4 aut
700	0		\|a Kieu Lam \|e verfasserin \|4 aut
700	0		\|a Marlen Lepper \|e verfasserin \|4 aut
700	0		\|a Melanie Adler \|e verfasserin \|4 aut
700	0		\|a Tracy Meffen \|e verfasserin \|4 aut
700	0		\|a James Heyes \|e verfasserin \|4 aut
700	0		\|a Katalin Karikó \|e verfasserin \|4 aut
700	0		\|a Pete Lutwyche \|e verfasserin \|4 aut
700	0		\|a Irena Vlatkovic \|e verfasserin \|4 aut
773	0	8	\|i In \|t Biomedicines \|d MDPI AG, 2014 \|g 11(2023), 6, p 1735 \|w (DE-627)750370483 \|w (DE-600)2720867-9 \|x 22279059 \|7 nnns
773	1	8	\|g volume:11 \|g year:2023 \|g number:6, p 1735
856	4	0	\|u https://doi.org/10.3390/biomedicines11061735 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/25fe821524ea47a48910c484bef99572 \|z kostenfrei
856	4	0	\|u https://www.mdpi.com/2227-9059/11/6/1735 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/2227-9059 \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_31
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 11 \|j 2023 \|e 6, p 1735

Indexfelder

author_variant	o d od a j m ajm s m sm k m km j r jr g b gb g t s gts j r jr p s ps s r sr k l kl m l ml m a ma t m tm j h jh k k kk p l pl i v iv
matchkey_str	article:22279059:2023----::smnlphrpuifrhtetetfriioucnccdranbesr
hierarchy_sort_str	2023
callnumber-subject-code	QH
publishDate	2023
allfields	10.3390/biomedicines11061735 doi (DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572 DE-627 ger DE-627 rakwb eng QH301-705.5 Owen Daly verfasserin aut ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA. lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General) Azita Josefine Mahiny verfasserin aut Sara Majeski verfasserin aut Kevin McClintock verfasserin aut Julia Reichert verfasserin aut Gábor Boros verfasserin aut Gábor Tamás Szabó verfasserin aut Jonas Reinholz verfasserin aut Petra Schreiner verfasserin aut Steve Reid verfasserin aut Kieu Lam verfasserin aut Marlen Lepper verfasserin aut Melanie Adler verfasserin aut Tracy Meffen verfasserin aut James Heyes verfasserin aut Katalin Karikó verfasserin aut Pete Lutwyche verfasserin aut Irena Vlatkovic verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 6, p 1735 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:6, p 1735 https://doi.org/10.3390/biomedicines11061735 kostenfrei https://doaj.org/article/25fe821524ea47a48910c484bef99572 kostenfrei https://www.mdpi.com/2227-9059/11/6/1735 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 6, p 1735
spelling	10.3390/biomedicines11061735 doi (DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572 DE-627 ger DE-627 rakwb eng QH301-705.5 Owen Daly verfasserin aut ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA. lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General) Azita Josefine Mahiny verfasserin aut Sara Majeski verfasserin aut Kevin McClintock verfasserin aut Julia Reichert verfasserin aut Gábor Boros verfasserin aut Gábor Tamás Szabó verfasserin aut Jonas Reinholz verfasserin aut Petra Schreiner verfasserin aut Steve Reid verfasserin aut Kieu Lam verfasserin aut Marlen Lepper verfasserin aut Melanie Adler verfasserin aut Tracy Meffen verfasserin aut James Heyes verfasserin aut Katalin Karikó verfasserin aut Pete Lutwyche verfasserin aut Irena Vlatkovic verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 6, p 1735 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:6, p 1735 https://doi.org/10.3390/biomedicines11061735 kostenfrei https://doaj.org/article/25fe821524ea47a48910c484bef99572 kostenfrei https://www.mdpi.com/2227-9059/11/6/1735 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 6, p 1735
allfields_unstemmed	10.3390/biomedicines11061735 doi (DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572 DE-627 ger DE-627 rakwb eng QH301-705.5 Owen Daly verfasserin aut ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA. lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General) Azita Josefine Mahiny verfasserin aut Sara Majeski verfasserin aut Kevin McClintock verfasserin aut Julia Reichert verfasserin aut Gábor Boros verfasserin aut Gábor Tamás Szabó verfasserin aut Jonas Reinholz verfasserin aut Petra Schreiner verfasserin aut Steve Reid verfasserin aut Kieu Lam verfasserin aut Marlen Lepper verfasserin aut Melanie Adler verfasserin aut Tracy Meffen verfasserin aut James Heyes verfasserin aut Katalin Karikó verfasserin aut Pete Lutwyche verfasserin aut Irena Vlatkovic verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 6, p 1735 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:6, p 1735 https://doi.org/10.3390/biomedicines11061735 kostenfrei https://doaj.org/article/25fe821524ea47a48910c484bef99572 kostenfrei https://www.mdpi.com/2227-9059/11/6/1735 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 6, p 1735
allfieldsGer	10.3390/biomedicines11061735 doi (DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572 DE-627 ger DE-627 rakwb eng QH301-705.5 Owen Daly verfasserin aut ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA. lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General) Azita Josefine Mahiny verfasserin aut Sara Majeski verfasserin aut Kevin McClintock verfasserin aut Julia Reichert verfasserin aut Gábor Boros verfasserin aut Gábor Tamás Szabó verfasserin aut Jonas Reinholz verfasserin aut Petra Schreiner verfasserin aut Steve Reid verfasserin aut Kieu Lam verfasserin aut Marlen Lepper verfasserin aut Melanie Adler verfasserin aut Tracy Meffen verfasserin aut James Heyes verfasserin aut Katalin Karikó verfasserin aut Pete Lutwyche verfasserin aut Irena Vlatkovic verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 6, p 1735 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:6, p 1735 https://doi.org/10.3390/biomedicines11061735 kostenfrei https://doaj.org/article/25fe821524ea47a48910c484bef99572 kostenfrei https://www.mdpi.com/2227-9059/11/6/1735 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 6, p 1735
allfieldsSound	10.3390/biomedicines11061735 doi (DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572 DE-627 ger DE-627 rakwb eng QH301-705.5 Owen Daly verfasserin aut ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA. lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General) Azita Josefine Mahiny verfasserin aut Sara Majeski verfasserin aut Kevin McClintock verfasserin aut Julia Reichert verfasserin aut Gábor Boros verfasserin aut Gábor Tamás Szabó verfasserin aut Jonas Reinholz verfasserin aut Petra Schreiner verfasserin aut Steve Reid verfasserin aut Kieu Lam verfasserin aut Marlen Lepper verfasserin aut Melanie Adler verfasserin aut Tracy Meffen verfasserin aut James Heyes verfasserin aut Katalin Karikó verfasserin aut Pete Lutwyche verfasserin aut Irena Vlatkovic verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 6, p 1735 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:6, p 1735 https://doi.org/10.3390/biomedicines11061735 kostenfrei https://doaj.org/article/25fe821524ea47a48910c484bef99572 kostenfrei https://www.mdpi.com/2227-9059/11/6/1735 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 6, p 1735
language	English
source	In Biomedicines 11(2023), 6, p 1735 volume:11 year:2023 number:6, p 1735
sourceStr	In Biomedicines 11(2023), 6, p 1735 volume:11 year:2023 number:6, p 1735
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD) Biology (General)
isfreeaccess_bool	true
container_title	Biomedicines
authorswithroles_txt_mv	Owen Daly @@aut@@ Azita Josefine Mahiny @@aut@@ Sara Majeski @@aut@@ Kevin McClintock @@aut@@ Julia Reichert @@aut@@ Gábor Boros @@aut@@ Gábor Tamás Szabó @@aut@@ Jonas Reinholz @@aut@@ Petra Schreiner @@aut@@ Steve Reid @@aut@@ Kieu Lam @@aut@@ Marlen Lepper @@aut@@ Melanie Adler @@aut@@ Tracy Meffen @@aut@@ James Heyes @@aut@@ Katalin Karikó @@aut@@ Pete Lutwyche @@aut@@ Irena Vlatkovic @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	750370483
id	DOAJ094202230
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ094202230</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240413031227.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biomedicines11061735</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ094202230</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ25fe821524ea47a48910c484bef99572</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QH301-705.5</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Owen Daly</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">lipid nanoparticle-mRNA (LNP-mRNA)</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA optimization</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA therapeutic</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">rare disease</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">argininosuccinic aciduria (ASA)</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">argininosuccinate lyase deficiency (ASLD)</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Biology (General)</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Azita Josefine Mahiny</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sara Majeski</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kevin McClintock</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Julia Reichert</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Gábor Boros</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Gábor Tamás Szabó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jonas Reinholz</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Petra Schreiner</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Steve Reid</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kieu Lam</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marlen Lepper</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Melanie Adler</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tracy Meffen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">James Heyes</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Katalin Karikó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pete Lutwyche</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Irena Vlatkovic</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomedicines</subfield><subfield code="d">MDPI AG, 2014</subfield><subfield code="g">11(2023), 6, p 1735</subfield><subfield code="w">(DE-627)750370483</subfield><subfield code="w">(DE-600)2720867-9</subfield><subfield code="x">22279059</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:11</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:6, p 1735</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biomedicines11061735</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/25fe821524ea47a48910c484bef99572</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2227-9059/11/6/1735</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2227-9059</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">11</subfield><subfield code="j">2023</subfield><subfield code="e">6, p 1735</subfield></datafield></record></collection>
callnumber-first	Q - Science
author	Owen Daly
spellingShingle	Owen Daly misc QH301-705.5 misc lipid nanoparticle-mRNA (LNP-mRNA) misc mRNA optimization misc mRNA therapeutic misc rare disease misc argininosuccinic aciduria (ASA) misc argininosuccinate lyase deficiency (ASLD) misc Biology (General) ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
authorStr	Owen Daly
ppnlink_with_tag_str_mv	@@773@@(DE-627)750370483
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut
collection	DOAJ
remote_str	true
callnumber-label	QH301-705
illustrated	Not Illustrated
issn	22279059
topic_title	QH301-705.5 ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model lipid nanoparticle-mRNA (LNP-mRNA) mRNA optimization mRNA therapeutic rare disease argininosuccinic aciduria (ASA) argininosuccinate lyase deficiency (ASLD)
topic	misc QH301-705.5 misc lipid nanoparticle-mRNA (LNP-mRNA) misc mRNA optimization misc mRNA therapeutic misc rare disease misc argininosuccinic aciduria (ASA) misc argininosuccinate lyase deficiency (ASLD) misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc lipid nanoparticle-mRNA (LNP-mRNA) misc mRNA optimization misc mRNA therapeutic misc rare disease misc argininosuccinic aciduria (ASA) misc argininosuccinate lyase deficiency (ASLD) misc Biology (General)
topic_browse	misc QH301-705.5 misc lipid nanoparticle-mRNA (LNP-mRNA) misc mRNA optimization misc mRNA therapeutic misc rare disease misc argininosuccinic aciduria (ASA) misc argininosuccinate lyase deficiency (ASLD) misc Biology (General)
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Biomedicines
hierarchy_parent_id	750370483
hierarchy_top_title	Biomedicines
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)750370483 (DE-600)2720867-9
title	ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
ctrlnum	(DE-627)DOAJ094202230 (DE-599)DOAJ25fe821524ea47a48910c484bef99572
title_full	ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
author_sort	Owen Daly
journal	Biomedicines
journalStr	Biomedicines
callnumber-first-code	Q
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2023
contenttype_str_mv	txt
author_browse	Owen Daly Azita Josefine Mahiny Sara Majeski Kevin McClintock Julia Reichert Gábor Boros Gábor Tamás Szabó Jonas Reinholz Petra Schreiner Steve Reid Kieu Lam Marlen Lepper Melanie Adler Tracy Meffen James Heyes Katalin Karikó Pete Lutwyche Irena Vlatkovic
container_volume	11
class	QH301-705.5
format_se	Elektronische Aufsätze
author-letter	Owen Daly
doi_str_mv	10.3390/biomedicines11061735
author2-role	verfasserin
title_sort	asl mrna-lnp therapeutic for the treatment of argininosuccinic aciduria enables survival benefit in a mouse model
callnumber	QH301-705.5
title_auth	ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
abstract	Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
abstractGer	Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
abstract_unstemmed	Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
container_issue	6, p 1735
title_short	ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
url	https://doi.org/10.3390/biomedicines11061735 https://doaj.org/article/25fe821524ea47a48910c484bef99572 https://www.mdpi.com/2227-9059/11/6/1735 https://doaj.org/toc/2227-9059
remote_bool	true
author2	Azita Josefine Mahiny Sara Majeski Kevin McClintock Julia Reichert Gábor Boros Gábor Tamás Szabó Jonas Reinholz Petra Schreiner Steve Reid Kieu Lam Marlen Lepper Melanie Adler Tracy Meffen James Heyes Katalin Karikó Pete Lutwyche Irena Vlatkovic
author2Str	Azita Josefine Mahiny Sara Majeski Kevin McClintock Julia Reichert Gábor Boros Gábor Tamás Szabó Jonas Reinholz Petra Schreiner Steve Reid Kieu Lam Marlen Lepper Melanie Adler Tracy Meffen James Heyes Katalin Karikó Pete Lutwyche Irena Vlatkovic
ppnlink	750370483
callnumber-subject	QH - Natural History and Biology
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.3390/biomedicines11061735
callnumber-a	QH301-705.5
up_date	2024-07-03T21:50:35.352Z
_version_	1803596265277095936
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ094202230</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240413031227.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biomedicines11061735</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ094202230</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ25fe821524ea47a48910c484bef99572</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QH301-705.5</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Owen Daly</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL<sup<Neo/Neo</sup< mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">lipid nanoparticle-mRNA (LNP-mRNA)</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA optimization</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mRNA therapeutic</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">rare disease</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">argininosuccinic aciduria (ASA)</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">argininosuccinate lyase deficiency (ASLD)</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Biology (General)</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Azita Josefine Mahiny</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sara Majeski</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kevin McClintock</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Julia Reichert</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Gábor Boros</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Gábor Tamás Szabó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jonas Reinholz</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Petra Schreiner</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Steve Reid</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kieu Lam</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marlen Lepper</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Melanie Adler</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tracy Meffen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">James Heyes</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Katalin Karikó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pete Lutwyche</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Irena Vlatkovic</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomedicines</subfield><subfield code="d">MDPI AG, 2014</subfield><subfield code="g">11(2023), 6, p 1735</subfield><subfield code="w">(DE-627)750370483</subfield><subfield code="w">(DE-600)2720867-9</subfield><subfield code="x">22279059</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:11</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:6, p 1735</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biomedicines11061735</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/25fe821524ea47a48910c484bef99572</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2227-9059/11/6/1735</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2227-9059</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">11</subfield><subfield code="j">2023</subfield><subfield code="e">6, p 1735</subfield></datafield></record></collection>
score	7.40226

Nicht das Richtige dabei?

Schreiben Sie uns!

ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?