mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5

Hauser, Stefan; Poenisch, Marion; Schelling, Yvonne; Höflinger, Philip; Schuster, Stefanie; Teegler, Axel; Betten, Rabea; Gustafsson, Jan Åke; Hübener‐Schmid, Jeannette; Schlake, Thomas; Chevessier-Tünnesen, Frédéric; Horscroft, Nigel; Björkhem, Ingemar; Schöls, Lüdger

doi:10.1016/j.omtm.2019.10.011

Cited by 24 publications

(29 citation statements)

References 35 publications

(48 reference statements)

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“… 66 Such advances have contributed–in part–to the pioneering successes that are starting to be realized for in vivo delivery of therapeutic mRNA outside of the vaccine arena. 67 − 72 …”

Section: Discussionmentioning

confidence: 99%

Exquisitely Specific anti-KRAS Biodegraders Inform on the Cellular Prevalence of Nucleotide-Loaded States

et al. 2020

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Mutations to RAS proteins (H-, N-, and K-RAS) are among the most common oncogenic drivers, and tumors harboring these lesions are some of the most difficult to treat. Although covalent small molecules against KRAS G12C have shown promising efficacy against lung cancers, traditional barriers remain for drugging the more prevalent KRAS G12D and KRAS G12V mutants. Targeted degradation has emerged as an attractive alternative approach, but for KRAS, identification of the required high-affinity ligands continues to be a challenge. Another significant hurdle is the discovery of a hybrid molecule that appends an E3 ligase-recruiting moiety in a manner that satisfies the precise geometries required for productive polyubiquitin transfer while maintaining favorable druglike properties. To gain insights into the advantages and feasibility of KRAS targeted degradation, we applied a protein-based degrader (biodegrader) approach. This workflow centers on the intracellular expression of a chimeric protein consisting of a high-affinity target-binding domain fused to an engineered E3 ligase adapter. A series of anti-RAS biodegraders spanning different RAS isoform/nucleotide-state specificities and leveraging different E3 ligases provided definitive evidence for RAS degradability. Further, these established that the functional consequences of KRAS degradation are context dependent. Of broader significance, using the exquisite degradation specificity that biodegraders can possess, we demonstrated how this technology can be applied to answer questions that other approaches cannot. Specifically, application of the GDP-state specific degrader uncovered the relative prevalence of the “off-state” of WT and various KRAS mutants in the cellular context. Finally, if delivery challenges can be addressed, anti-RAS biodegraders will be exciting candidates for clinical development.

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Section: Discussionmentioning

confidence: 99%

Exquisitely Specific anti-KRAS Biodegraders Inform on the Cellular Prevalence of Nucleotide-Loaded States

et al. 2020

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“…Obtaining sufficient delivery and intracellular expression will be amongst the most important challenges. Encouragingly, the in vivo delivery of therapeutic mRNA is starting to be realized outside of the vaccine arena [55][56][57][58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

bioPROTACs establish RAS as a degradable target and provide novel RAS biology insights

Lim¹,

Khoo²,

Juang³

et al. 2020

Preprint

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Mutations to RAS proteins (H-, N-, and K-RAS) are amongst the most common oncogenic drivers and tumors harboring these lesions are some of the most difficult to treat. Although the recently discovered covalent small molecules against the KRAS G12C mutant have shown promising efficacy against lung cancers, traditional barriers remain for drugging the more prevalent KRAS G12D and KRAS G12V mutants. Targeted degradation has emerged as an attractive alternative approach but for KRAS, identification of the required high-affinity ligands continues to be a challenge. Another significant hurdle is the discovery of a hybrid molecule that appends an E3 ligase-recruiting moiety in a manner that satisfies the precise geometries required for productive polyubiquitin transfer while maintaining favorable druglike properties. As a tool to gain insights into the advantages and feasibility of KRAS targeted-degradation, we applied the bioPROTAC approach. This workflow centers on the intracellular expression of a chimeric protein consisting of a high-affinity target-binding domain fused to an engineered E3 ligase adapter. We generated a series of anti-RAS bioPROTACs that span different RAS isoform/nucleotide-state specificities and leverage different E3 ligases. Overall, our results provide definitive evidence for the degradability of RAS proteins. We further elucidate the functional consequences of RAS degradation, the susceptibility and degradation kinetics of various mutant KRAS, and the prevalence of different nucleotide-states in WT and mutant KRAS. Finally, if delivery challenges can be addressed, anti-RAS bioPROTACs will be exciting candidates for clinical development.

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“…Preclinical studies also showed the potential of mRNA‐based therapy in inherited spastic paraplegia type 5. [ 193 ] Additionally, a hybrid mRNA technology delivery system has been developed to treat ornithine transcarbamylase (OTC) deficiency. [ 178 ] This mRNA delivery system consists of two types of nanoparticles: a di‐block polymer micelle ( N ‐acetylgalactosamine (GalNAc)‐targeted polymer micelle) that targets liver and promotes transfection, and an inert LNP composed of DOTAP/CHEMS/Chol/PEG2k‐lipid to encapsulate mRNA and protect it from nucleases.…”

Section: Application and Clinical Translationmentioning

confidence: 99%

Nanoplatforms for mRNA Therapeutics

Meng

Chen

et al. 2020

Advanced Therapeutics

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mRNA‐based therapeutics are a unique class of drugs for treatment of human diseases. Since in vitro transcribed mRNA molecules have relatively low stability and their surface charge prevents them from direct cell entry, they need to be packaged into specially designed delivery platforms to exert their activities. Multiple nanotechnology‐based delivery platforms have been developed for mRNA delivery, such as polymer‐based polyplex, lipid‐based lipoplex, and lipid‐coated polymer‐based lipopolyplex. In this review, an overview of the nanoplatforms for mRNA delivery is provided. A number of applications in biotechnology including cell reprogramming and gene editing are also described. In addition, their clinical translational potential for protein replacement therapy and for infectious disease and cancer treatment is introduced.

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mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5

Cited by 24 publications

References 35 publications

Exquisitely Specific anti-KRAS Biodegraders Inform on the Cellular Prevalence of Nucleotide-Loaded States

Exquisitely Specific anti-KRAS Biodegraders Inform on the Cellular Prevalence of Nucleotide-Loaded States

bioPROTACs establish RAS as a degradable target and provide novel RAS biology insights

Nanoplatforms for mRNA Therapeutics

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