Abstract Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer’s disease in astrocytes and for coronary artery disease in hepatocytes. In vivo prime editing with v3em PE-AAV caused no detectable off-target effects or significant changes in liver enzymes or histology. Optimized PE-AAV systems support the highest unenriched levels of in vivo prime editing reported to date, facilitating the study and potential treatment of diseases with a genetic component. 

/pdf/efficient-prime-editing-in-mouse-brain-liver-and-heart-with-2glq7l34.pdf

Efficient prime editing in mouse brain, liver and heart with dual AAVs

Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient in vitro and in vivo delivery of prime editing components, however, remains a challenge. Here we report prime editor engineered virus-like particles (PE-eVLPs) that deliver prime editor proteins, prime editing guide RNAs and nicking single guide RNAs as transient ribonucleoprotein complexes. We systematically engineered v3 and v3b PE-eVLPs with 65- to 170-fold higher editing efficiency in human cells compared to a PE-eVLP construct based on our previously reported base editor eVLP architecture. In two mouse models of genetic blindness, single injections of v3 PE-eVLPs resulted in therapeutically relevant levels of prime editing in the retina, protein expression restoration and partial visual function rescue. Optimized PE-eVLPs support transient in vivo delivery of prime editor ribonucleoproteins, enhancing the potential safety of prime editing by reducing off-target editing and obviating the possibility of oncogenic transgene integration. 

Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo.

In this article, an efficient difference scheme for the coupled fractional Ginzburg–Landau equations with the fractional Laplacian is studied. We construct the discrete scheme based on the implicit midpoint method in time and a weighted and shifted Grünwald difference method in space. Then, we prove that the scheme is uniquely solvable, and the numerical solutions are bounded and unconditionally convergent in the lh2 norm. Finally, numerical tests are given to confirm the theoretical results and show the effectiveness of the scheme.

An efficient difference scheme for the coupled nonlinear fractional Ginzburg–Landau equations with the fractional Laplacian

Exact solutions of the stochastic fractional long-short wave interaction system with multiplicative noise in generalized elastic medium

(2 < p < 4) [200]. (Uq(∫u(1, 1)), oq1/2(2n)) [92]. 1 [273, 79, 304, 119]. 1 + 1 [252]. 2 [352, 318, 226, 40, 233, 157, 299, 60]. 2× 2 [185]. 3 [456, 363, 58, 18, 351]. ∗ [238]. 2 [277]. 3 [350]. p [282]. B−L [427]. α [216, 483]. α− z [322]. N = 2 [507]. D [222]. ẍ+ f(x)ẋ + g(x) = 0 [112, 111, 8, 5, 6]. Eτ,ηgl3 [148]. g [300]. κ [244]. L [205, 117]. L [164]. L∞ [368]. M [539]. P [27]. R [147]. Z2 [565]. Z n 2 [131]. Z2 × Z2 [25]. D(X) [166]. S(N) [110]. ∫l2 [154]. SU(2) [210]. N [196, 242]. O [386]. osp(1|2) [565]. p [113, 468]. p(x) [17]. q [437, 220, 92, 183]. R, d = 1, 2, 3 [279]. SDiff(S) [32]. σ [526]. SLq(2) [185]. SU(N) [490]. τ [440]. U(1) N [507]. Uq(sl 2) [185]. φ 2k [283]. φ [553]. φ4 [365]. ∨ [466]. VOA[M4] [33]. Z [550].

/pdf/a-complete-bibliography-of-publications-in-the-journal-of-3brkwhz8a7.pdf

A Complete Bibliography of Publications in the Journal of Mathematical Physics: 2005{2009

Retinitis pigmentosa (RP) is an inherited retinal dystrophy causing progressive and irreversible loss of retinal photoreceptors. Here, we developed a genome-editing tool characterized by the versatility of prime editors (PEs) and unconstrained PAM requirement of a SpCas9 variant (SpRY), referred to as PESpRY. The diseased retinas of Pde6b-associated RP mouse model were transduced via a dual AAV system packaging PESpRY for the in vivo genome editing through a non-NGG PAM (GTG). The progressing cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6β. The treated mice exhibited significant responses in electroretinogram and displayed good performance in both passive and active avoidance tests. Moreover, they presented an apparent improvement in visual stimuli-driven optomotor responses and efficiently completed visually guided water-maze tasks. Together, our study provides convincing evidence for the prevention of vision loss caused by RP-associated gene mutations via unconstrained in vivo prime editing in the degenerating retinas.

Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas.

This paper is concerned with the stochastic coupled fractional Ginzburg-Landau equation with additive noise. We first transform the stochastic coupled fractional Ginzburg-Landau equation into random equations whose solutions generate a random dynamical system. Then we prove the existence of random attractor for random dynamical system.

Random attractors for the stochastic coupled fractional Ginzburg-Landau equation with additive noise

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Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas.

Random attractors for the stochastic coupled fractional Ginzburg-Landau equation with additive noise