Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification
The acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disea...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-01-01
|
| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116300488 |
| _version_ | 1818083908159275008 |
|---|---|
| author | Amy Chan Abigail Liebow Makiko Yasuda Lin Gan Tim Racie Martin Maier Satya Kuchimanchi Don Foster Stuart Milstein Klaus Charisse Alfica Sehgal Muthiah Manoharan Rachel Meyers Kevin Fitzgerald Amy Simon Robert J Desnick William Querbes |
| author_facet | Amy Chan Abigail Liebow Makiko Yasuda Lin Gan Tim Racie Martin Maier Satya Kuchimanchi Don Foster Stuart Milstein Klaus Charisse Alfica Sehgal Muthiah Manoharan Rachel Meyers Kevin Fitzgerald Amy Simon Robert J Desnick William Querbes |
| author_sort | Amy Chan |
| collection | DOAJ |
| description | The acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disease symptoms. We have demonstrated that hepatic ALAS1 silencing using siRNA in a lipid nanoparticle effectively prevents and treats induced attacks in a mouse model of acute intermittent porphyria. Herein, we report the development of ALN-AS1, an investigational GalNAc-conjugated RNAi therapeutic targeting ALAS1. One challenge in advancing ALN-AS1 to patients is the inability to detect liver ALAS1 mRNA in the absence of liver biopsies. We here describe a less invasive circulating extracellular RNA detection assay to monitor RNAi drug activity in serum and urine. A striking correlation in ALAS1 mRNA was observed across liver, serum, and urine in both rodents and nonhuman primates (NHPs) following treatment with ALN-AS1. Moreover, in donor-matched human urine and serum, we demonstrate a notable correspondence in ALAS1 levels, minimal interday assay variability, low interpatient variability from serial sample collections, and the ability to distinguish between healthy volunteers and porphyria patients with induced ALAS1 levels. The collective data highlight the potential utility of this assay in the clinical development of ALN-AS1, and in broadening our understanding of acute hepatic porphyrias disease pathophysiology. |
| first_indexed | 2024-12-10T19:45:28Z |
| format | Article |
| id | doaj.art-39568a2964f14544a20cb66549c751d3 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-10T19:45:28Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-39568a2964f14544a20cb66549c751d32022-12-22T01:35:54ZengElsevierMolecular Therapy: Nucleic Acids2162-25312015-01-014C10.1038/mtna.2015.36Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA QuantificationAmy Chan0Abigail Liebow1Makiko Yasuda2Lin Gan3Tim Racie4Martin Maier5Satya Kuchimanchi6Don Foster7Stuart Milstein8Klaus Charisse9Alfica Sehgal10Muthiah Manoharan11Rachel Meyers12Kevin Fitzgerald13Amy Simon14Robert J Desnick15William Querbes16Alnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USAAlnylam Pharmaceuticals, Cambridge, Massachusetts, USAThe acute hepatic porphyrias are caused by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that cause disease symptoms. We have demonstrated that hepatic ALAS1 silencing using siRNA in a lipid nanoparticle effectively prevents and treats induced attacks in a mouse model of acute intermittent porphyria. Herein, we report the development of ALN-AS1, an investigational GalNAc-conjugated RNAi therapeutic targeting ALAS1. One challenge in advancing ALN-AS1 to patients is the inability to detect liver ALAS1 mRNA in the absence of liver biopsies. We here describe a less invasive circulating extracellular RNA detection assay to monitor RNAi drug activity in serum and urine. A striking correlation in ALAS1 mRNA was observed across liver, serum, and urine in both rodents and nonhuman primates (NHPs) following treatment with ALN-AS1. Moreover, in donor-matched human urine and serum, we demonstrate a notable correspondence in ALAS1 levels, minimal interday assay variability, low interpatient variability from serial sample collections, and the ability to distinguish between healthy volunteers and porphyria patients with induced ALAS1 levels. The collective data highlight the potential utility of this assay in the clinical development of ALN-AS1, and in broadening our understanding of acute hepatic porphyrias disease pathophysiology.http://www.sciencedirect.com/science/article/pii/S2162253116300488RNAiGalNAc-conjugated siRNAexosomecirculating RNAheme biosynthetic disorder |
| spellingShingle | Amy Chan Abigail Liebow Makiko Yasuda Lin Gan Tim Racie Martin Maier Satya Kuchimanchi Don Foster Stuart Milstein Klaus Charisse Alfica Sehgal Muthiah Manoharan Rachel Meyers Kevin Fitzgerald Amy Simon Robert J Desnick William Querbes Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification Molecular Therapy: Nucleic Acids RNAi GalNAc-conjugated siRNA exosome circulating RNA heme biosynthetic disorder |
| title | Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification |
| title_full | Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification |
| title_fullStr | Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification |
| title_full_unstemmed | Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification |
| title_short | Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification |
| title_sort | preclinical development of a subcutaneous alas1 rnai therapeutic for treatment of hepatic porphyrias using circulating rna quantification |
| topic | RNAi GalNAc-conjugated siRNA exosome circulating RNA heme biosynthetic disorder |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116300488 |
| work_keys_str_mv | AT amychan preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT abigailliebow preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT makikoyasuda preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT lingan preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT timracie preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT martinmaier preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT satyakuchimanchi preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT donfoster preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT stuartmilstein preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT klauscharisse preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT alficasehgal preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT muthiahmanoharan preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT rachelmeyers preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT kevinfitzgerald preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT amysimon preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT robertjdesnick preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification AT williamquerbes preclinicaldevelopmentofasubcutaneousalas1rnaitherapeuticfortreatmentofhepaticporphyriasusingcirculatingrnaquantification |