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Table 1 Different treatment strategies currently in use for conformational disorders

From: Disorders of FZ-CRD; insights towards FZ-CRD folding and therapeutic landscape

Treatment Strategies Description
Gene therapy Gene therapy involves replacing the mutant copy of the gene with a wild-type functional protein.
Gene editing CRISPR/Cas9 is a gene-editing strategy where only the mutated sequence of a mutant gene is edited and thereby corrected for proper function of the protein.
Gene correction in iPSCs Using specialized induced pluripotent stem cells (iPSCs), CRISPR/Cas9 editing allows the correction of the gene within iPSCs increasing effectiveness of the technique.
Modulator Therapies--using differing mechanisms of action- Modulators can be either potentiators, correctors [pharmacological chaperones & proteostasis regulators], stabilizers, or amplifiers.
Modulators are pharmaceutical agents that targets specific defects in the mutant protein and/or modulate the intracellular environment.
  • Modulators target protein errors that occur post-transcriptionally, such as during protein folding, anterograde trafficking and further assist protein function and signaling following protein expression.
Correctors improve intracellular processing of misfolded proteins and increase plasma membrane expression.
Potentiators and stabilizers help the misfolded protein once expressed. Combination therapies with different mechanisms of actions, show greater efficacy.
  • Proteostasis regulators improve the overall quality of the proteostasis network within a cell.
Regulators can be designed to increase the function and availability of molecular chaperones, and consequently promote protein folding and/or reduce misfolding.
Regulators targeting the ER quality control can enhance the elimination of non-native conformations of polypeptides.
Stem cell therapy Stem cell therapy is a tailored approach which is easy to proliferate and modify. It can further be coupled with CIRSPR/Cas9 and correct cells to a WT phenotype in the correct cell-line.
Antisense-oligonucleotide-mediated therapy Single-stranded synthetic RNA-like molecules known as antisense oligonucleotides (ASOs) selectively change gene expression.
Non-viral vectors Non-viral vectors have the ability to pack and deliver bulky DNA molecules with liposomal vectors.
mRNA-mediated therapy Wild-type nucleotide sequence is targeted to the cell and has the ability to encode wild-type protein.
Proteasome inhibitors Inhibition of proteasome, a unique proteolytic complex, prevents degradation of ubiquitinated proteins tagged for ERAD.