Table 1 Different treatment strategies currently in use for conformational disorders

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.