Systemic messenger RNA as an etiological treatment for acute intermittent porphyria

Jiang, Lei; Berraondo, Pedro; Jericó, Daniel; Guey, Lin T.; Sampedro, Ana; Frassetto, Andrea; Benenato, Kerry E.; Burke, Kristine; Santamaría, Eva; Alegre, Manuel; Pejenaute, Álvaro; Kalariya, Mayur; Butcher, William; Park, Ji-Sun; Zhu, Xinwen; Sabnis, Staci; Kumarasinghe, E. Sathyajith; Salerno, Timothy; Kenney, Matthew G.; Lukacs, C.M.; Ávila, Matías A.; Martini, Paolo G.V.; Fontanellas, Antonio

doi:10.1038/s41591-018-0199-z

Cited by 146 publications

(157 citation statements)

References 40 publications

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“…From a translational perspective, since the mean duration of an acute attack was reported between 5 and 7 days in patients with AIP,47 hPBGD mRNA offers a promising alternative to treat acute attacks. Moreover, administration of equivalent doses of the mRNA was well tolerated and reached the same efficacy in rat, rabbit and monkey (75% increase over endogenous activity) 9. In the case of maintaining the same gain in humans (patient’s liver shows 50% of healthy livers’ endogenous activity), normal PBGD activity would be achieved and the accumulation of neurotoxic precursors could be avoided.…”

Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 83%

“…Human PBGD showed therapeutic levels in the liver of AIP mice for 7–10 days at the doses tested 9. From a translational perspective, since the mean duration of an acute attack was reported between 5 and 7 days in patients with AIP,47 hPBGD mRNA offers a promising alternative to treat acute attacks.…”

Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 91%

“…However, porphyrin precursor overexcretion was not modified in eight patients enrolled in a phase I open-label, multicentre clinical trial,46 indicating that sufficient delivery of the transgene was not achieved in humans and that more efficient vectors are needed. A recent preclinical study demonstrated that the intravenous administration of a human PBGD mRNA encapsulated in biodegradable LNPs (figure 4) induced high protein expression and enzyme activity in mouse livers in less than 2 hours 9. The therapeutic efficacy of this strategy was put forward in AIP mice and a rabbit model of the disease where the rapid expression of PBGD protein in the liver induced normalisation of both ALA/PBG excretion in hours and a full protection against pain and motor neuropathy.…”

Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 99%

“…Immunohistochemical analysis of the hepatocyte distribution on intravenous administration of mRNA encapsulated in LNPs in mouse models has demonstrated that virtually all hepatocytes can be reached 9. An alternative liver-targeting technology dubbed the hybrid mRNA technology delivery system (HMT) has been recently proposed.…”

Section: Introductionmentioning

confidence: 99%

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Messenger RNA therapy for rare genetic metabolic diseases

Berraondo

Martini

Avila

et al. 2019

Gut

Self Cite

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Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.

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Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 83%

Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 91%

Section: Rare Genetic Metabolic Diseases: Difficult To Treat Conditiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Messenger RNA therapy for rare genetic metabolic diseases

Berraondo

Martini

Avila

et al. 2019

Gut

Self Cite

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show abstract

“…Recently, the field of AIP therapy has been revolutionized by two groundbreaking papers. The first is a preclinical study using intravenous human PBGD (hPBGD) mRNA encapsulated in lipid nanoparticles (Moderna Therapeutics, Cambrdige, MA) to transduce liver cells . The second is a phase 2 clinical trial using a small interfering RNA (siRNA) (givosiran; Alnylam Pharmaceuticals, Cambridge, MA) directed against hepatic ALAS1 mRNA (Fig.…”

mentioning

confidence: 99%

Acute Intermittent Porphyria: Novel Etiologic and Pathogenic Therapies Based on RNA Transfer to the Liver

Prìeto

González‐Aseguinolaza

2019

Hepatology

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When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population

Sriretnakumar,

Harripaul,

Kennedy

et al. 2024

American J of Med Genetics Pt A

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Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next‐generation sequencing of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 48 putative affected and 180 putative carriers for TGDs were identified, with known or likely pathogenic variants in 79 genes. Despite screening for only 108 genetic disorders, this study showed a two‐fold (2.09%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases is greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.

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Systemic messenger RNA as an etiological treatment for acute intermittent porphyria

Cited by 146 publications

References 40 publications

Messenger RNA therapy for rare genetic metabolic diseases

Messenger RNA therapy for rare genetic metabolic diseases

Acute Intermittent Porphyria: Novel Etiologic and Pathogenic Therapies Based on RNA Transfer to the Liver

When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population

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