| 000 | 02512 am a22003493u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aBöck, Desirée _eauthor _92742 |
| 700 | 1 | 0 |
_aRothgangl, Tanja _eauthor _92743 |
| 700 | 1 | 0 |
_aVilliger, Lukas _eauthor _92744 |
| 700 | 1 | 0 |
_aSchmidheini, Lukas _eauthor _92745 |
| 700 | 1 | 0 |
_aMatsushita, Mai _eauthor _92746 |
| 700 | 1 | 0 |
_aMathis, Nicolas _eauthor _92747 |
| 700 | 1 | 0 |
_aIoannidi, Eleonora _eauthor _92748 |
| 700 | 1 | 0 |
_aRimann, Nicole _eauthor _92749 |
| 700 | 1 | 0 |
_aGrisch-Chan, Hiu Man _eauthor _92750 |
| 700 | 1 | 0 |
_aKreutzer, Susanne _eauthor _92751 |
| 700 | 1 | 0 |
_aKontarakis, Zacharias _eauthor _92752 |
| 700 | 1 | 0 |
_aKopf, Manfred _eauthor _92753 |
| 700 | 1 | 0 |
_aThöny, Beat _eauthor _92754 |
| 700 | 1 | 0 |
_aSchwank, Gerald _eauthor _92755 |
| 245 | 0 | 0 | _aIn vivo prime editing of a metabolic liver disease in mice |
| 260 | _c2022-03-16. | ||
| 500 | _a/pmc/articles/PMC7614134/ | ||
| 500 | _a/pubmed/35294257 | ||
| 520 | _aPrime editing is a highly versatile CRISPR-based genome editing technology that works without DNA double-strand break formation. Despite rapid technological advances, in vivo application for the treatment of genetic diseases remains challenging. Here, we developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain (PE2(ΔRnH)) and an intein-split construct (PE2 p.1153) for adeno-associated virus (AAV)-mediated delivery into the liver. Editing efficiencies reached 15% at the Dnmt1 locus, and were further elevated to 58% by delivering unsplit PE2(ΔRnH) via human adenoviral vector 5 (AdV). To provide proof-of-concept for correcting a genetic liver disease, we next employed the AdV approach for repairing the disease-causing Pah(enu2) mutation in a mouse model of phenylketonuria (PKU) via prime editing. Average correction efficiencies of 11.1% (up to 17.4%) in neonates led to therapeutic reduction of blood phenylalanine (L-Phe), without inducing detectable off-target mutations or prolonged liver inflammation. Although the current in vivo prime editing approach for PKU has limitations for clinical application due to the requirement of high vector doses (7×10(14) vg/kg) and the induction of immune responses to the vector and the PE, further development of the technology may lead to curative therapies for PKU and other genetic liver diseases. | ||
| 540 | _a | ||
| 546 | _aen | ||
| 690 | _aArticle | ||
| 655 | 7 |
_aText _2local |
|
| 786 | 0 | _nSci Transl Med | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1126/scitranslmed.abl9238 _zConnect to this object online. |
| 999 |
_c2242 _d2242 |
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