KARAKTERISTIKE KLINIČKIH ISPITIVANJA GENSKE TERAPIJE IZ JAVNIH KLINIČKIH REGISTRA

Autor: Zlatin, Michael
Přispěvatelé: Marušić, Ana, Sapunar, Damir, Pranić, Shelly, Pavlinac Dodig, Ivana
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Popis: Objectives: To analyze technological and ethical aspects of studies involving modern gene editing therapies registered in public trial registries: genetic diseases targeted for gene therapy; technologies used (CRISPR, ZFN, TALEN, viral vectors); status; if modern methods for off target and on target mutations were used as part of safety assessment: transparency of the trials, based on availability of publications, results posted to registry, IPD sharing and completeness of data. Methods: Registries were searched for “gene editing” and “genome editing” and eligible trials were analyzed. Results: 42 trials for single gene diseases were analyzed, and their characteristics were presented in tables. Zinc Finger Nuclease (ZFN) with adeno associated virus vector (AAV) was used for gene editing in vivo. CRISPR and ZFN techniques were used for ex vivo editing (autologous and allogeneic), mostly in Hematopoietic Stem Cells and CAR T cells. Most of the trials were open label, Phase 1 or 1/2, with 17% completed, one of them getting FDA approval. 21% withdrawn, terminated or of unknown status. Two of the studies, done in China, did editing on germline cells with major ethics violations, and one of them resulted in birth of genetically edited babies. Almost all trials did not post results to registry, did not share Individual Patient Data, and most lacked publications that reflected content of the trials. Conclusion: Advancements in gene editing techniques such as ZFN, CRISPR/Cas9, and use of safer viral vectors (AAV) as delivery system decreased the risk of insertional mutagenesis and cytotoxicity, and made possible genetic therapy of single gene disorders in humans, with various cancers, HIV, sickle cell disease, and thalassemia being the most often investigated. First gene therapy drug, approved by FDA for spinal muscular atrophy, Zolgensma, sets the standard for gene therapies, including high price and FDA warning for liver toxicity. Lack of results posted to registries, lack of publications that reflect content of the trial, unwillingness to share IPD, and incomplete data show the low level of transparency in gene editing trials. Measures to increase transparency, for example, proposed by World Health Organization creation of special registry dedicated to gene therapy and gene editing trials are needed.
Ciljevi: Analizirati tehnološke i etičke aspekte studija koje uključuju moderne terapije uređivanja gena registrirane u javnim registrima ispitivanja: genetske bolesti ciljane za gensku terapiju; korištene tehnologije (CRISPR, ZFN, TALEN); transparentnost. Metode: Pretraženi su registri i odabrana i analizirana prihvatljiva klinička ispitivanja. Rezultati: Analizirana su 42 ispitivanja za niz bolesti, uključujući rak i HIV, a njihove su karakteristike prikazane u tablicama. CRISPR i ZFN tehnike korištene su za ex vivo uređivanje (autologne i alogene), uglavnom u matičnim stanicama hematopoeze i CAR T stanicama. ZFN s adeno povezanim virusnim vektorom (AAV) korišten je za uređivanje gena in vivo. Većina pokusa bila su otvorene, faza 1 ili 1/2, sa 17% dovršeno, od kojih je jedno dobilo odobrenje FDA; i 21% povučeno, ukinuto ili nepoznatog statusa. Dvije studije, rađene u Kini, uređivale su stanice zametnih linija s velikim kršenjem etike, a jedna od njih rezultirala je rođenjem genetski uređenih beba. Gotovo sva ispitivanja nisu objavila rezultate u registru, nisu dijelila pojedinačne podatke o pacijentima, a većini su nedostajale publikacije koje su odražavale sadržaj ispitivanja. Zaključci: Napredak u tehnikama uređivanja gena kao što su ZFN i CRISPR / Cas9 i upotreba sigurnijih virusnih vektora (AAV) kao sustava isporuke, smanjili su rizik od insercijske mutageneze i citotoksičnosti te omogućili genetsku terapiju poremećaja jednog gena kod ljudi. Prvi lijek za gensku terapiju, koji je odobrila FDA, Zolgensma, postavlja standarde za genske terapije, uključujući vrlo visoku cijenu. Nedostatak rezultata objavljenih u registrima, nedostatak publikacija koje odražavaju sadržaj ispitivanja, nespremnost za dijeljenje IPD-a, pokazuju nisku razinu transparentnosti u ispitivanjima uređivanja gena. Potrebne su mjere za povećanje transparentnosti, na primjer, koje je predložila Svjetska zdravstvena organizacija, stvaranje posebnog registra posvećenog genskoj terapiji i ispitivanjima uređivanja gena.
Databáze: OpenAIRE
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