Inherited Bone Marrow Failure Syndromes

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1	Inherited bone marrow failure syndromes are a group diseases characterized by peripheral cytopenias and associated with cancerogenesis. No therapies for IBMFS have been developed so far.	Valentino Bezzerri	+ 1764 word(s)	1764	2020-07-03 05:01:09	\|
2	format correct	Nora Tang	-9 word(s)	1755	2020-11-19 04:23:18	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms21134672

Inherited bone marrow failure syndromes (IBMFS) are a group of cancer prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. Unofrtunately, no pharmacological therapies have been developed for IBMFS so far and bone marrow hematopoietic stem cell transplant remains the unique option to correct bone marrow failure and prevent myeloid neoplasia.

bone marrow nonsense mutations rare diseases ataluren Fanconi Anemia Dyskeratosis Congenita Diamond-Blackfan Anemia Shwachman-Diamond Syndrome Severe Congenital Neutropenia

1. Introduction

Inherited bone marrow failure syndromes (IBMFS) are cancer prone disorders characterized by peripheral cytopenia(s) with a hypocellular bone marrow and impairment in one or more hematopoietic lineages. The classical IBMFS are represented by Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). Importantly, 10–15% of bone marrow aplasia and 30% of pediatric bone marrow failure disorders are caused by IBMFS, with approximately 65 cases per million live births every year ^[1]. However, emerging data reveal that IBMFS are underdiagnosed because of decreased recognition or because genetic mutation associated with congenital bone marrow failure are detected only after a malignancy has arisen ^[2].

Clinical management of IBMFS requires multidisciplinary care and surveillance to detect early emergence of malignancies. Early hematopoietic stem cell transplant (HCT) may correct bone marrow failure and prevent the development of myeloid neoplasia, but it does not affect the risk of solid tumors. However, post-HCT complications, such as graft-versus-host disease and immune dysfunction, frequently occur. As an alternative to HCT, androgen administration may be suitable for patients with FA and DC. Corticosteroids are often effective for patients with DBA, especially for those who lack a compatible donor or are ineligible for HCT transplantation. In addition, recombinant granulocyte colony-stimulating factor (G-CSF) is used to ameliorate severe neutropenia in SCN or SDS and prevent recurrent infections. Long-term use of G-CSF in SCN and SDS has been associated with increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) ^[3]. No therapies to reduce bone marrow failure or cancer risk in IBMFS have been developed so far.

It has been estimated that approximately 12% of human genetic disorders are caused by single-nucleotide or out-of-frame nonsense mutations, leading to the generation of premature termination codons (PTC). Correct protein synthesis normally represents the core of biological process for any living organism. For this reason, protein synthesis is regulated at multiple levels and any disruption on each of these steps may cause severe diseases. The therapeutic strategy aimed at overcoming PTC has been defined as “nonsense suppression therapy”. This approach is intended to generate the readthrough of PTC, restoring a full-length protein synthesis. Alternatively, nonsense suppression therapy may be designed to reduce the nonsense mediated decay (NMD) induced by the nonsense mutations. NMD is an evolutionarily conserved defense mechanism of eukaryotic cells that surveys newly synthesized mRNA and degrades transcripts containing a PTC ^[4]^[5].

Bezzerri and colleagues tested the efficacy of a small nonsense suppressor molecule, ataluren (PTC124, PTC Therapeutics, NJ) [6], in correcting the basic defect of SDS with promising preclinical results. That preclinical study might serve as proof of concept for the development of nonsense suppression therapy for other IBMFS.

2. Development

2.1. Inherited Bone Marrow Failure Syndromes

Bone marrow failure syndromes (BMFS) cluster different disorders characterized by impaired hematopoiesis which lead to selective or global cytopenia. BMFS may be acquired, such as aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PHN), or congenital. IBMFS are classified into those that result in pancytopenia and those limited to deficiency of one or more hematopoietic lineages. FA and DC are characterized by progressive peripheral pancytopenia. Patients with DBA exhibit anemia, whereas SDS and SCN are mostly associated with severe neutropenia. Some of the IBMFS can be characterized by physical anomalies and failure to thrive. IBMFS are all associated with increased risk for the development of MDS/AML and solid tumors.

Approximately 80 different genes have been associated with different IBMFS ^[6]. Notably, 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC mutated alleles show nonsense pathogenic variants (Figure 1). Classes of genes correlate with specific IBMFS, such as genes which encode for proteins involved in DNA repair (FA), telomere biology (DC), and ribosome biogenesis (DBA). Many cancers have been associated with somatic mutations in genes encoding ribosomal proteins ^[7]. Importantly, defective ribosomal proteins may induce the upregulation of the tumor suppressor gene TP53 which encode the tumor suppressor protein p53 ^[8]^[9]. In this regard, p53 over-activation has been implicated in the pathogenesis of DBA, SDS, and DC ^[10]^[11]^[12].

Figure 1. Incidence of nonsense mutations in inherited bone marrow failure syndromes (IBMFS). Percentages have been calculated on the basis of ClinVar database ^[13]. Only pathogenic and likely pathogenic variants have been taken into account.

2.2. The Nonsense Suppression Therapy

The termination of eukaryotic translation process requires the recognition of a stop codon into the A (aminoacyl) site of ribosome by specific aminoacyl-tRNA bounded to eukaryotic translation termination factor 1 (eRF1) and GTP. Rarely, translational mistakes, defined as mispairing, could occur when a near-cognate aminoacyl-tRNA, whose anticodon is complementary just for two of the three nucleotides of a stop codon, improperly binds the stop codon. This process, defined “readthrough”, leads to the incorporation of an amino acid into the nascent polypeptide chain preventing the normal termination of translation. It has been estimated that the endogenous readthrough take place in 0.001% to 0.1% of total tranlsation processes and 0.01% to 1% generally occurs at the PTC ^[14]^[15]^[16]. It follows that PTC may be endogenously inhibited by the natural readthrough leading to a random substitution of the eRF1 with a near-cognate (nc)-tRNA ^[17]^[18]. Several factors can affect the readthrough process, including the sequence of nucleotides upstream and downstream the stop codon. It has been observed that the nucleotide which immediately follows the termination codon in the 3′ direction (position +4, considering the first nucleotide of stop codon as +1) is involved in the interactions between mRNA and the translational machinery ^[19]^[20]^[21]. For instance, studies conducted in yeasts have suggested that cytosine at position +4 negatively affect the recognition of eRF1 on the stop codon ^[22]. Additionally, nucleotides located at positions +5, +6 and +9 can influence the translational readthrough. The relative abundance of various near-cognate aminoacyl-tRNAs is another important aspect ^[23].

3. Discussion and Perspectives

No pharmacological therapies designed specifically against an IBMFS have been developed yet. The application of gene therapy and induced pluripotent stem cells (iPS) sounds promising. At least two lentiviral gene-based trials are recruiting for the treatment of Fanconi anemia (NCT01331018 and NCT03157804). In addition, gene editing has recently raised interest of IBMFS community. The correction of FANCA, FANCC, FANCD1/BRCA2, FANCI, and FANCF pathogenic variants by CRISPR-Cas9 gene editing has been demonstrated in vitro ^[24]^[25]^[26]^[27]. Gene editing approach based on CRISPR/Cas9-sgRNA has also been recently shownto reduce ELANE expression ex vivo in bone marrow hematopoietic progenitors from patients with SCN. CRISPR-Cas9-mediated knockdown of ELANE significantly induced neutrophil maturation in vitro ^[28]. It should be nevertheless noted that CRISPR-Cas9 technology presents several limitations for its rapid translation as a therapy, including cell type dependent delivery, incomplete efficiency of homologous recombination and the possibility of off-target editing ^[29].

Because 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC mutated alleles (Figure 1) carry nonsense mutations in IBMFS-related genes, Bezzerri and colleagues proposed another approach, that of nonsense suppressor therapy. Nonsense suppression therapy used in non-hematologic genetic diseases such as DMD and CF. Ataluren (Translarna^®) is an approved drug for the treatment of DMD and, importantly, several Phase II/III clinical studies reported very low toxicity of ataluren even in pediatric patients aged two and older ^[30]^[31]^[32]^[33]^[34]^[35]^[36].

Little is known about their effect on IBMFS. It has been already reported that ataluren improves SBDS full-length protein synthesis and function in bone marrow hematopoietic progenitors and mesenchymal stromal cells isolated from bone marrow biopsies of patients with SDS .

PTC-readthrough inducer molecules generally exhibit low efficiency. Although ataluren showed encouraging preclinical results in CF models, restoring CFTR protein synthesis and chloride function, the clinical development has been subsequently discontinued because of poor clinical benefits in terms of respiratory function improvement. A post hoc subgroup analysis demonstrated that a sub-cohort of patients treated with ataluren reported some clinical benefit. A recent clinical study showed that a partial synergistic effect of ivacaftor and ataluren can be observed in terms of improvement of nasal potential difference, although the major limitation of this study was the very little number (only two) of patients tested ^[32].

Ataluren however failed in a model of Dravet syndrome, an autosomal dominant form of epilepsy, perhaps because of codon selectivity. Its efficacy may depend on the sequence of PTC (UAA<UAG<UGA) ^[37]^[38]. Interestingly, both aniridia and SDS models, where ataluren significantly improved the target protein synthesis and function with promising in vivo and ex vivo results, shared the same stop codon, namely UGA, which is the hypothetical best sequence. Alternatively, readthrough efficacy may depend on the tissue and cell type targeted by the therapy ^[39]. Positive responses from blood cells derived from both aniridia and SDS justify the use of ataluren in other IBMFS.

Besides ataluren, several other readthrough inducer molecules have been synthesized and preclinically tested so far. Some ataluren analogues have shown increased in vitro efficacy compared to ataluren ^[40]^[41]. However, little is known about the toxicity of these molecules and further studies are needed to clarify this important step in drug development.

Another strategy aimed at restoring nonsense mutated transcripts is due by NMD inhibitors. However, as previously discussed, since the endogenous readthrough occurs very infrequently, a therapeutic approach aimed only at inhibiting the NMD, without increasing the readthrough capability, might not be sufficient for clinical purposes. One strategy would be to combine the two approaches to enhance full-length protein synthesis from transcripts of nonsense-mutated genes. For example, PTC-readthrough enhancers may potentiate the effect of reathrough-inducer drugs.

L-leucine administration improved the anemiain rps19-deficient zebrafish model of DBA by activating the mTOR pathway ^[42]. Moreover, L-leucine treatment has been proposed to activate translation of erythroid cells, improving globin gene synthesis and ameliorating the anemic phenotype in rps19 and rpl11 mutants in zebrafish ^[43]. These studies support a Phase I/II clinical trial (NCT01362595) that evaluates the effect of L-leucine supplementation on red blood cell transfusion dependent DBA patients. Since L-leucine may promote protein synthesis in erythroid cells, combinationtherapy of L-leucine, NMD inhibitors and/or PTC-readthrough inducers could improve the anemia of DBA.

All these premises suggest therefore that nonsense suppression therapy should be tested in IBMFS with hopeful expectations. Even if only preclinical positive results have been achieved so far, they should be considered as new important proof of concepts for extending the current therapeutic scenario for IBMFS.

References

Neelam Giri; Pamela Stratton; Sharon A. Savage; Blanche P. Alter; Pregnancies in patients with inherited bone marrow failure syndromes in the NCI cohort. Blood 2017, 130, 1674-1676, 10.1182/blood-2017-08-802991.
Sk Hashmi; C Allen; R Klaassen; Cv Fernandez; R Yanofsky; E Shereck; J Champagne; M Silva; Jh Lipton; J Brossard; et al.Y SamsonS AbishM SteeleK AliN DowerU AthaleL JardineJp HandJ BeyeneY Dror Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clinical Genetics 2011, 79, 448-458, 10.1111/j.1399-0004.2010.01468.x.
Rodrigo Tocantins Calado; Diego Clé; Treatment of inherited bone marrow failure syndromes beyond transplantation. Hematology 2017, 2017, 96-101, 10.1182/asheducation-2017.1.96.
Fabrice Lejeune; Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Reports 2017, 50, 175-185, 10.5483/BMBRep.2017.50.4.015.
Monica Borgatti; Emiliano Altamura; Francesca Salvatori; Elisabetta D’Aversa; Nicola Altamura; Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia. Journal of Clinical Medicine 2020, 9, 289, 10.3390/jcm9020289.
Sharon A. Savage; Carlo Dufour; Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia. Seminars in Hematology 2017, 54, 105-114, 10.1053/j.seminhematol.2017.04.004.
Ram Ajore; David Raiser; Marie McConkey; Magnus Jöud; Bernd Boidol; Brenton Mar; Gordon Saksena; David M Weinstock; Scott Armstrong; Steven R Ellis; et al.Benjamin L. EbertBjörn Nilsson Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP 53 mutations. EMBO Molecular Medicine 2017, 9, 498-507, 10.15252/emmm.201606660.
Sergey O. Sulima; Kim R. Kampen; Kim De Keersmaecker; Cancer Biogenesis in Ribosomopathies. Cells 2019, 8, 229, 10.3390/cells8030229.
Joy Armistead; Barbara Triggs‐Raine; Diverse diseases from a ubiquitous process: The ribosomopathy paradox. FEBS Letters 2014, 588, 1491-1500, 10.1016/j.febslet.2014.03.024.
Yigal Dror; P53 protein overexpression in Shwachman-Diamond syndrome.. Archives of Pathology & Laboratory Medicine 2002, 126, 1157, 10.1043/1543-2165(2002)126<1157b:PPOISS>2.0.CO;2.
M Tarek Elghetany; Blanche P. Alter; p53 protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia.. Archives of Pathology & Laboratory Medicine 2002, 126, 452-455, 10.1043/0003-9985(2002)126<0452:PPOIBM>2.0.CO;2.
Daniel C. Link; Mechanisms of leukemic transformation in congenital neutropenia. Current Opinion in Hematology 2019, 26, 34-40, 10.1097/moh.0000000000000479.
Melissa Landrum; Jennifer M Lee; Mark Benson; Garth R Brown; Chen Chao; Shanmuga Chitipiralla; Baoshan Gu; Jennifer Hart; Uglas Hoffman; Wonhee Jang; et al.Karen KarapetyanKenneth KatzChunlei LiuZenith MaddipatlaAdriana MalheiroKurt McDanielMichael OvetskyGeorge R RileyGeorge ZhouJ Bradley HolmesBrandi L KattmanNna R Maglott ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Research 2017, 46, D1062-D1067, 10.1093/nar/gkx1153.
Brian Bonetti; Karl Fu; James Moon; David M. Bedwell; The Efficiency of Translation Termination is Determined by a Synergistic Interplay Between Upstream and Downstream Sequences inSaccharomyces cerevisiae. Journal of Molecular Biology 1995, 251, 334-345, 10.1006/jmbi.1995.0438.
Michel Cassan; Jean-Pierre Rousset; UAG readthrough in mammalian cells: Effect of upstream and downstream stop codon contexts reveal different signals. BMC Molecular Biology 2001, 2, 3-3, 10.1186/1471-2199-2-3.
Marina Manuvakhova; Kim Keeling; D M Bedwell; Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system.. RNA 2000, 6, 1044-1055, 10.1017/s1355838200000716.
Maciej Dabrowski; Zuzanna Bukowy-Bieryllo; Ewa Zietkiewicz; Translational readthrough potential of natural termination codons in eucaryotes – The impact of RNA sequence. RNA Biology 2015, 12, 950-958, 10.1080/15476286.2015.1068497.
K Fearon; V McClendon; B Bonetti; D M Bedwell; Premature translation termination mutations are efficiently suppressed in a highly conserved region of yeast Ste6p, a member of the ATP-binding cassette (ABC) transporter family.. Journal of Biological Chemistry 1994, 269, 17802-17808.
K. K. McCaughan; Chris M. Brown; M. E. Dalphin; M. J. Berry; W. P. Tate; Translational termination efficiency in mammals is influenced by the base following the stop codon.. Proceedings of the National Academy of Sciences 1995, 92, 5431-5435, 10.1073/pnas.92.12.5431.
Irwin Jungreis; Michael F. Lin; Rebecca Spokony; Clara S. Chan; Nicolas Nègre; Alec Victorsen; Kevin P. White; Manolis Kellis; Evidence of abundant stop codon readthrough in Drosophila and other metazoa.. Genes & Development 2011, 21, 2096-113, 10.1101/gr.119974.110.
Gary Loughran; Ming-Yuan Chou; Ivaylo P. Ivanov; Irwin Jungreis; Manolis Kellis; Anmol M. Kiran; Pavel V. Baranov; John F. Atkins; Evidence of efficient stop codon readthrough in four mammalian genes.. Nucleic Acids Research 2014, 42, 8928-38, 10.1093/nar/gku608.
Petra Beznosková; Stanislava Gunišová; Leoš Shivaya Valášek; Rules of UGA-N decoding by near-cognate tRNAs and analysis of readthrough on short uORFs in yeast. RNA 2016, 22, 456-466, 10.1261/rna.054452.115.
Maciej Dabrowski; Zuzanna Bukowy-Bieryllo; Ewa Zietkiewicz; Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Molecular Medicine 2018, 24, 25, 10.1186/s10020-018-0024-7.
Mark J. Osborn; Richard Gabriel; Beau R. Webber; Anthony P. Defeo; Amber N. McElroy; Jordan Jarjour; Colby G. Starker; John E. Wagner; J. Keith Joung; Daniel F. Voytas; et al.Christof Von KalleManfred SchmidtBruce R. BlazarJakub Tolar Fanconi Anemia Gene Editing by the CRISPR/Cas9 System. Human Gene Therapy 2015, 26, 114-126, 10.1089/hum.2014.111.
Mark J. Osborn; Cara-Lin Lonetree; Beau R. Webber; Dharmeshkumar Patel; Samantha Dunmire; Anthony P. Defeo; Amber N. McElroy; Margaret L. Macmillan; John E. Wagner; Bruce R. Blazar; et al.Jakub Tolar CRISPR/Cas9 Targeted Gene Editing and Cellular Engineering in Fanconi Anemia. Stem Cells and Development 2016, 25, 1591-1603, 10.1089/scd.2016.0149.
Karolina Skvarova Kramarzova; Mark J. Osborn; Beau R. Webber; Anthony P. Defeo; Amber N. McElroy; Chong Jai Kim; Jakub Tolar; CRISPR/Cas9-Mediated Correction of the FANCD1 Gene in Primary Patient Cells. International Journal of Molecular Sciences 2017, 18, 1269, 10.3390/ijms18061269.
Paula Rio; Rocío Baños; A. Lombardo; Oscar Quintana-Bustamante; Lara Alvarez; Zita Garate; Pietro Genovese; Elena Almarza; Antonio Valeri; Begoña Díez; et al.Susana NavarroYaima TorresJuan P TrujilloRodolfo MurillasJosé Carlos SegoviaEnrique SamperJordi SurrallésPhilip GregoryMichael C HolmesLuigi NaldiniJuan Antonio Bueren Targeted gene therapy and cell reprogramming in F anconi anemia. EMBO Molecular Medicine 2014, 6, 835-848, 10.15252/emmm.201303374.
Masoud Nasri; Malte Ritter; Perihan Mir; Benjamin Dannenmann; Narges Aghaallaei; Diana Amend; Vahagn Makaryan; Yun Xu; Breanna Fletcher; Regine Bernhard; et al.Ingeborg SteiertKarin HahnelJürgen BergerIris KochBrigitte SailerKatharina HippCornelia ZeidlerMaksim KlimiankouBaubak BajoghliDavid C. DaleKarl WelteJulia Skokowa CRISPR/Cas9-mediated ELANE knockout enables neutrophilic maturation of primary hematopoietic stem and progenitor cells and induced pluripotent stem cells of severe congenital neutropenia patients. Haematologica 2019, 105, 598-609, 10.3324/haematol.2019.221804.
Duran Sürün; H Von Melchner; Frank Schnütgen; CRISPR/Cas9 genome engineering in hematopoietic cells. Drug Discovery Today: Technologies 2018, 28, 33-39, 10.1016/j.ddtec.2018.08.001.
Craig McDonald; Craig Campbell; Ricardo Erazo Torricelli; Richard S. Finkel; Kevin Flanigan; Nathalie Goemans; Peter Heydemann; Anna Kostera-Pruszczyk; Janbernd Kirschner; Francesco Muntoni; et al.Andrés Nascimento OsorioUlrike ScharaThomas SejersenPerry B. ShiehH L SweeneyHaluk TopalogluMár TuliniusJuan Jesús VílchezThomas VoitBrenda WongGary ElfringHans KrögerXiaohui LuoJoseph McIntoshTuyen OngPeter RieblingMárcio SouzaRobert J SpiegelStuart W PeltzEugenio MercuriLindsay N. AlfanoMichelle EagleMeredith K JamesLinda P LowesA. MayhewElena S MazzoneLeslie NelsonKristy J. RoseHoda Z Abdel-HamidSusan D ApkonRichard J BarohnEnrico BertiniClemens BloetzerLausanne Canton De VaudRussell J ButterfieldBrigitte ChabrolJong-Hee ChaeDaehak-Ro Jongno-GuGiacomi Pietro ComiBasil DarrasJahannaz DastgirIsabelle DesguerreRaul G EscobarErika FinangerMichela GuglieriImelda HughesSusan T. IannacconeKristi J JonesPeter KarachunskiMartin KudrTimothy LotzeJean K MahKatherine MathewsYoram NevoJulie ParsonsYann PereonAlexandra Prufer De Queiroz Campos AraujoJ Ben RenfroeMaria Bernadete Dutra De ResendeMonique RyanKathryn SelbyGihan TennekoonGiuseppe Vita Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2017, 390, 1489-1498, 10.1016/s0140-6736(17)31611-2.
M.W. Konstan; E. DiMango; E. Kerem; P. Melotti; S. Rowe; I. Sermet-Gaudelus; M. Wilschanski; J. McIntosh; Y. Sun; K. De Boeck; et al. WS13.3 Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: the international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). Journal of Cystic Fibrosis 2017, 16, S23-S24, 10.1016/s1569-1993(17)30233-3.
Jacelyn E. Peabody Lever; Venkateshwar Mutyam; Heather Y. Hathorne; Ning Peng; Jyoti Sharma; Lloyd J. Edwards; Steven M. Rowe; Ataluren/ivacaftor combination therapy: Two N‐of‐1 trials in cystic fibrosis patients with nonsense mutations. Pediatric Pulmonology 2020, 55, 1838-1842, 10.1002/ppul.24764.
Richard S. Finkel; Kevin Flanigan; Brenda Wong; Carsten Bönnemann; Jacinda Sampson; H. Lee Sweeney; Allen Reha; Valerie J. Northcutt; Gary Elfring; Jay Barth; et al.Stuart W. Peltz Phase 2a Study of Ataluren-Mediated Dystrophin Production in Patients with Nonsense Mutation Duchenne Muscular Dystrophy. PLOS ONE 2013, 8, e81302, 10.1371/journal.pone.0081302.
Eitan Kerem; Michael W. Konstan; Kris De Boeck; Frank J. Accurso; Isabelle Sermet-Gaudelus; Michael Wilschanski; J. Stuart Elborn; Paola Melotti; Inez Bronsveld; I. Fajac; et al.Anne MalfrootDaniel B. RosenbluthPatricia A. WalkerSusanna A. McColleyChristiane KnoopSerena QuattrucciErnst RietschelPamela L. Zeitlin MdJay BarthGary L. ElfringEllen M. WelchArthur BranstromRobert J. SpiegelStuart W. PeltzTemitayo AjayiSteven M. RoweCystic Fibrosis Ataluren Study Group Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.. The Lancet Respiratory Medicine 2014, 2, 539-47, 10.1016/S2213-2600(14)70100-6.
Ronald Kong; Oscar L. Laskin; Diksha Kaushik; Fengbin Jin; Jiyuan Ma; Joseph McIntosh; Marcio Souza; Neil Almstead; Ataluren Pharmacokinetics in Healthy Japanese and Caucasian Subjects. Clinical Pharmacology in Drug Development 2019, 8, 172-178, 10.1002/cpdd.645.
Eugenio Mercuri; Francesco Muntoni; Andrés Nascimento Osorio; Már Tulinius; Filippo Buccella; Lauren P Morgenroth; Heather Gordish-Dressman; Joel Jiang; Panayiota Trifillis; Jin Zhu; et al.Allan KristensenClaudio L SantosErik K HenricsonCraig M McDonaldIsabelle DesguerreOn Behalf Of The Stride‡CINRG Duchenne Natural History Investigators§ Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study.. Journal of Comparative Effectiveness Research 2020, 9, 341-360, 10.2217/cer-2019-0171.
Bijoyita Roy; Westley J. Friesen; Yuki Tomizawa; John D. Leszyk; Jin Zhuo; Briana Johnson; Jumana Dakka; Christopher R. Trotta; Xiaojiao Xue; Venkateshwar Mutyam; et al.Kim M. KeelingJames A. MobleySteven M. RoweDavid M. BedwellEllen M. WelchAllan Jacobson Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression.. Proceedings of the National Academy of Sciences 2016, 113, 12508-12513, 10.1073/pnas.1605336113.
Iwona Pranke; Laure Bidou; Natacha Martin; Sandra Blanchet; Aurélie Hatton; Sabrina Karri; David Cornu; Bruno Costes; Benoît Chevalier; Danielle Tondelier; et al.Emmanuelle GirodonMatthieu CoupetAleksander EdelmanPascale FanenOlivier NamyIsabelle Sermet-GaudelusAlexandre Hinzpeter Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons. ERJ Open Research 2018, 4, 00080-2017, 10.1183/23120541.00080-2017.
Vaughn Thada; Jake N. Miller; Attila D. Kovács; David A. Pearce; Tissue‐specific variation in nonsense mutant transcript level and drug‐induced read‐through efficiency in the Cln1 R151X mouse model of INCL. Journal of Cellular and Molecular Medicine 2016, 20, 381-385, 10.1111/jcmm.12744.
Ivana Pibiri; Laura Lentini; Raffaella Melfi; Giulia Gallucci; Andrea Pace; Angelo Spinello; Giampaolo Barone; Aldo Di Leonardo; Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives. European Journal of Medicinal Chemistry 2015, 101, 236-244, 10.1016/j.ejmech.2015.06.038.
Ivana Pibiri; Laura Lentini; Raffaella Melfi; Marco Tutone; Sara Baldassano; Paola Ricco Galluzzo; Aldo Di Leonardo; Andrea Pace; Rescuing the CFTR protein function: Introducing 1,3,4-oxadiazoles as translational readthrough inducing drugs. European Journal of Medicinal Chemistry 2018, 159, 126-142, 10.1016/j.ejmech.2018.09.057.
Elspeth M. Payne; Maria C. Virgilio; Anupama Narla; Hong Sun; Michelle Levine; Barry H. Paw; Nancy Berliner; A. Thomas Look; Benjamin L. Ebert; Arati Khanna-Gupta; et al. L-leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway. Blood 2012, 120, 2214-2224, 10.1182/blood-2011-10-382986.
Y Zhang; J Ear; Z Yang; K Morimoto; B Zhang; S Lin; Defects of protein production in erythroid cells revealed in a zebrafish Diamond-Blackfan anemia model for mutation in RPS19.. Cell Death & Disease 2014, 5, e1352-e1352, 10.1038/cddis.2014.318.

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Valentino Bezzerri

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Update Date: 19 Nov 2020

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