Table 1 Open in new tab Summary of... | Oxford Academic

Table 1

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Summary of potential therapeutic modalities for inherited arrhythmias

Parameter	Viral gene therapy	Oligonucleotides	Modified mRNA	Small molecules
Potential activities and benefits	Complex activity of genes and gene products Gene suppression; in some cases can selectively target a mutant allele Genome editing	Gene suppression; in some cases can selectively target a mutant allele Splicing modulation, e.g. exon skipping	Complex activity of genes and gene products	Modulation of enzymatic or channel activity Potential to disrupt protein–protein interactions
Specificity	Targeting to specific cells and subcellular compartments	Natural tropism for some cell types. Evolving capability for targeted delivery.	Natural tropism for some cell types. Evolving capability for targeted delivery.	Generally not targeted to specific cell types. Can be tailored by biophysical properties, e.g. exclusion by blood–brain barrier.
Dosing	Intravenous Catheter into coronary arteries or coronary veins	Parenteral injection	Currently direct intracardiac injection. Alternatives under development.	Oral or injected
Dosing frequency	Single dose. Methods for repeated dosing in development.	Weeks	Days	Typically hours to a day
Challenges	Transduction efficiency Transduced and untransduced cells create heterogeneous substrate that may lead to pro-arrhythmia Limited cargo capacity Pre-existing immunity Immune response to virus and cargo Durability over many years is not well-established Costly to manufacture	Toxicities related to oligonucleotide chemistries: thrombocytopenia, hepatotoxicity, nephrotoxicity, inflammatory effects Targeted expression not well-established	Need for repetitive dosing, likely by injection Targeted expression not well-established High doses may be necessary for clinical therapy	Limited range of biological activity Off-target activity

Parameter	Viral gene therapy	Oligonucleotides	Modified mRNA	Small molecules
Potential activities and benefits	Complex activity of genes and gene products Gene suppression; in some cases can selectively target a mutant allele Genome editing	Gene suppression; in some cases can selectively target a mutant allele Splicing modulation, e.g. exon skipping	Complex activity of genes and gene products	Modulation of enzymatic or channel activity Potential to disrupt protein–protein interactions
Specificity	Targeting to specific cells and subcellular compartments	Natural tropism for some cell types. Evolving capability for targeted delivery.	Natural tropism for some cell types. Evolving capability for targeted delivery.	Generally not targeted to specific cell types. Can be tailored by biophysical properties, e.g. exclusion by blood–brain barrier.
Dosing	Intravenous Catheter into coronary arteries or coronary veins	Parenteral injection	Currently direct intracardiac injection. Alternatives under development.	Oral or injected
Dosing frequency	Single dose. Methods for repeated dosing in development.	Weeks	Days	Typically hours to a day
Challenges	Transduction efficiency Transduced and untransduced cells create heterogeneous substrate that may lead to pro-arrhythmia Limited cargo capacity Pre-existing immunity Immune response to virus and cargo Durability over many years is not well-established Costly to manufacture	Toxicities related to oligonucleotide chemistries: thrombocytopenia, hepatotoxicity, nephrotoxicity, inflammatory effects Targeted expression not well-established	Need for repetitive dosing, likely by injection Targeted expression not well-established High doses may be necessary for clinical therapy	Limited range of biological activity Off-target activity

Table 1

Open in new tab

Summary of potential therapeutic modalities for inherited arrhythmias

Parameter	Viral gene therapy	Oligonucleotides	Modified mRNA	Small molecules
Potential activities and benefits	Complex activity of genes and gene products Gene suppression; in some cases can selectively target a mutant allele Genome editing	Gene suppression; in some cases can selectively target a mutant allele Splicing modulation, e.g. exon skipping	Complex activity of genes and gene products	Modulation of enzymatic or channel activity Potential to disrupt protein–protein interactions
Specificity	Targeting to specific cells and subcellular compartments	Natural tropism for some cell types. Evolving capability for targeted delivery.	Natural tropism for some cell types. Evolving capability for targeted delivery.	Generally not targeted to specific cell types. Can be tailored by biophysical properties, e.g. exclusion by blood–brain barrier.
Dosing	Intravenous Catheter into coronary arteries or coronary veins	Parenteral injection	Currently direct intracardiac injection. Alternatives under development.	Oral or injected
Dosing frequency	Single dose. Methods for repeated dosing in development.	Weeks	Days	Typically hours to a day
Challenges	Transduction efficiency Transduced and untransduced cells create heterogeneous substrate that may lead to pro-arrhythmia Limited cargo capacity Pre-existing immunity Immune response to virus and cargo Durability over many years is not well-established Costly to manufacture	Toxicities related to oligonucleotide chemistries: thrombocytopenia, hepatotoxicity, nephrotoxicity, inflammatory effects Targeted expression not well-established	Need for repetitive dosing, likely by injection Targeted expression not well-established High doses may be necessary for clinical therapy	Limited range of biological activity Off-target activity

Parameter	Viral gene therapy	Oligonucleotides	Modified mRNA	Small molecules
Potential activities and benefits	Complex activity of genes and gene products Gene suppression; in some cases can selectively target a mutant allele Genome editing	Gene suppression; in some cases can selectively target a mutant allele Splicing modulation, e.g. exon skipping	Complex activity of genes and gene products	Modulation of enzymatic or channel activity Potential to disrupt protein–protein interactions
Specificity	Targeting to specific cells and subcellular compartments	Natural tropism for some cell types. Evolving capability for targeted delivery.	Natural tropism for some cell types. Evolving capability for targeted delivery.	Generally not targeted to specific cell types. Can be tailored by biophysical properties, e.g. exclusion by blood–brain barrier.
Dosing	Intravenous Catheter into coronary arteries or coronary veins	Parenteral injection	Currently direct intracardiac injection. Alternatives under development.	Oral or injected
Dosing frequency	Single dose. Methods for repeated dosing in development.	Weeks	Days	Typically hours to a day
Challenges	Transduction efficiency Transduced and untransduced cells create heterogeneous substrate that may lead to pro-arrhythmia Limited cargo capacity Pre-existing immunity Immune response to virus and cargo Durability over many years is not well-established Costly to manufacture	Toxicities related to oligonucleotide chemistries: thrombocytopenia, hepatotoxicity, nephrotoxicity, inflammatory effects Targeted expression not well-established	Need for repetitive dosing, likely by injection Targeted expression not well-established High doses may be necessary for clinical therapy	Limited range of biological activity Off-target activity