RESUMO
DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Agboola, Fluetsch, Rind, and Pearson are employed by ICER. Lin reports support from ICER during work on this economic model and grants from Mount Zion Health Fund, National Institutes of Health (National Cancer Institute and National Heart, Lung, and Blood Institute), and the Tobacco-Related Diseases Research Program, unrelated to this work. Walton reports support from ICER for work on this economic model and unrelated consulting fees from Baxter.
Assuntos
Distrofina/genética , Imunossupressores/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Pregnenodionas/uso terapêutico , Análise Custo-Benefício , Éxons/efeitos dos fármacos , Éxons/genética , Humanos , Imunossupressores/economia , Modelos Econômicos , Morfolinos/economia , Morfolinos/farmacologia , Morfolinos/uso terapêutico , Distrofia Muscular de Duchenne/economia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/imunologia , Oligonucleotídeos/economia , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/economia , Oligonucleotídeos Antissenso/farmacologia , Prednisona/economia , Prednisona/uso terapêutico , Pregnenodionas/economia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoAssuntos
Terapia Genética/estatística & dados numéricos , Terapia de Alvo Molecular/estatística & dados numéricos , Ácidos Nucleicos/uso terapêutico , Medicina de Precisão/métodos , Adenoviridae/genética , Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Terapia Genética/economia , Genômica , Hemofilia A/classificação , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Humanos , Doença dos Neurônios Motores/tratamento farmacológico , Doença dos Neurônios Motores/genética , Mutação , Oligonucleotídeos Antissenso/economia , Oligonucleotídeos Antissenso/uso terapêutico , Quinolonas/uso terapêutico , Reino Unido/epidemiologiaRESUMO
In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending splice-switching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of "fusion therapies", including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
Assuntos
Distrofina/genética , Terapia Genética/métodos , Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Éxons/efeitos dos fármacos , Éxons/genética , Deleção de Genes , Humanos , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/terapia , Distrofia Muscular de Duchenne/genética , Oligonucleotídeos Antissenso/economia , Transplante de Células-Tronco/métodosRESUMO
Composite nucleic acids, known as 2-5A antisense chimeras, cause the 2-5A-dependent ribonuclease (RNase L) to catalyze the specific cleavage of RNA in cell free systems and in intact cells. Such 2-5A antisense chimeras are 5'-monophosphorylated, 2,'5'-linked oligoadenylates covalently attached to antisense 3',5'-oligodeoxyribonucleotides by means of a linker containing two residues of 1,4-butanediol phosphate. Here we report a fully automated synthesis of 2-5A antisense chimeras on a solid support using phosphoramidite methodology with specific coupling time modifications and their subsequent purification by reverse-phase ion-pair and anion exchange HPLC. Purified 2-5A antisense chimeras were characterized by [1H]NMR and [31P]NMR, MALDIMS, and capillary gel electrophoresis. The synthetic 2',5'-linked oligoadenylate showed no phosphodiester isomerization to 3',5' during or after synthesis. In addition, we have developed facile methodologies to characterize the chimeras using digestion with various hydrolytic enzymes including snake venom phosphodiesterase I and nuclease P1. Finally, Maxam-Gilbert chemical sequencing protocols have been developed to confirm the entire sequence of these chimeric oligonucleotides.