Application of Formulation Principles to Stability Issues Encountered During Processing, Manufacturing, and Storage of Drug Substance and Drug Product Protein Therapeutics

Vitharana, Skp; Stillahn, Joshua M.; Katayama, Derrick S.; Henry, Charles S.; Manning, Mark C.

doi:10.1016/j.xphs.2023.08.003

Cited by 4 publications

(2 citation statements)

References 712 publications

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“…We next loaded LNPs with Cas9 RNP (1:1 weight ratio Cas9 protein/sgRNA) or Cas9 mRNA (1:1 ratio mRNA/sgRNA) allowing a head-to-head comparison of both Cas9 formats. As the standard LNP microfluidic mixing and loading could not be employed as the ethanol and shear forces would denaturate the RNP, , we opted for a benchtop mixing approach where Cas9 mRNA and RNP were added to preformulated, empty LNPs. While this resulted in lower mRNA and RNP encapsulation efficiencies compared to conventional microfluidic mixing (18% for RNP and 31% for mRNA versus 93% mRNA with microfluidic mixing (Figure S1iv)), this proved sufficient for initial biological screening as previously demonstrated for siRNA .…”

Section: Results and Discussionmentioning

confidence: 99%

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Bolsoni,

Liu,

Mohabatpour

et al. 2023

ACS Nano

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Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for in situ gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10−16%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a pK a ∼ 7.1 yielded superior gene editing rates (55%−72%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%−12% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of ∼5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an in situ correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.

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Section: Results and Discussionmentioning

confidence: 99%

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Bolsoni,

Liu,

Mohabatpour

et al. 2023

ACS Nano

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“…For example, PROVENGE, an immune cell-based vaccine, has been approved by the US FDA to treat hormone-refractory prostate cancer ( Cheever and Higano, 2011 ). Studies have shown that storage conditions, formulation, stability in vivo , targeting, blood concentration, target concentration and other factors are important factors affecting the therapeutic effect of drugs ( Vitharana et al, 2023 ; Woodring et al, 2023 ). In the process of new drug research exploration, researchers have conducted more investigations for these factors and made great progress.…”

Section: Introductionmentioning

confidence: 99%

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment

Ren,

Su,

Shi

et al. 2023

Front. Bioeng. Biotechnol.

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Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide. Conventional treatments for HCC include drugs, radiation, and surgery. Despite the unremitting efforts of researchers, the curative effect of HCC has been greatly improved, but because HCC is often found in the middle and late stages, the curative effect is still not satisfactory, and the 5-year survival rate is still low. Nanomedicine is a potential subject, which has been applied to the treatment of HCC and has achieved promising results. Here, we summarized the factors affecting the efficacy of drugs in HCC treatment and the strategies for improving the efficacy of nanotechnology-based drugs in HCC, reviewed the recent applications’ progress on nanotechnology-based drugs in HCC treatment, and discussed the future perspectives and challenges of nanotechnology-based drugs in HCC treatment.

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Stability of Protein Pharmaceuticals: Recent Advances

Manning,

Holcomb,

Payne

et al. 2024

Pharm Res

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Application of Formulation Principles to Stability Issues Encountered During Processing, Manufacturing, and Storage of Drug Substance and Drug Product Protein Therapeutics

Cited by 4 publications

References 712 publications

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment

Stability of Protein Pharmaceuticals: Recent Advances

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