| Abstract | 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approval. 21% withdrawn, terminated or of unknown status.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. |
| Abstract (croatian) | 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. |
