Table 2.

Non-epigenetic approaches to modulating gene expression

Modality	Strengths	Weaknesses	Current status	Leading developer(s)	Best applications
Gene/Base/Prime Editing	High specificity Durable/permanent changes Can eliminate pathogenic gene expression and restore/augment expression	Off-target effects (incl DSBs) Limited options for delivery Redosability not possible at this time	1st gen approaches in POC clinical trials 2nd gen approaches in preclinical or early clinical dev	Editas Medicines CRISPR Therapeutics Intellia Therapeutics Beam Therapeutics Prime Medicines	Monogenic diseases with LOF mutations Oncology (ex vivo)
siRNA	Targeted (rational) design Redosable	Only reduces gene Expression Effect is short-lived Knockdown may be incomplete Off-target effects	5 Approved products (US) Many additional efficacy studies in progress	Alnylam Dicerna (Novo Nordisk) Arrowhead Pharmaceuticals	Liver/metabolic disease Infectious disease Rare disease with pathogenic overexpression
ASOs	Multiple MOAs	Less stable than siRNA Durability challenges Low potency Off-target effects	Multiple approved products (US)	lonis Pharmaceuticals Sarepta Therapeutics	Diseases caused by proteins with repeats Liver/metabolic disease Rare disease with pathogenic overexpression
Gene (replacement) therapy	Direct, precise upregulation	Limited options for delivery Redosability not possible at this time	2 approved products (US) Many additional pivotal studies in progress	Spark Therapeutics (Roche) AveXis (Novartis) BioMarin Pharmaceuticals Sangamo Therapeutics	Monogenic loss of function
Cell therapy	Clear connection to disease (known cell type, known modification)	Need appropriate cell type	Multiple approved products but limited to oncology	Novartis Gilead Sciences	Oncology (CAR-expressing cells)
Protein degraders	High tissue selectivity Multiple routes of delivery Well-understood chemistry and manufacturing	Only downregulation/protein reduction Potential for off-target effects	Early to mid-stage clinical development POC is emerging	Arvinas Monte Rosa Therapeutics	Oncology Neuroscience Immunology
Condensates	Differentiated MOA Novel targets	Emerging	Preclinical	Dewpoint Therapeutics Faze Medicines	Oncology Neuroscience/neuro-degeneration