Table 2 Non-epigenetic approaches to modulating gene expression
From: Drugging the epigenome in the age of precision medicine
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 |