Table 4.
Preclinical applications and clinical trials using gene editing for premature aging, metabolic, and immune response disorders.
| Disease | Target Gene | Editor | Delivery | Editing Efficiency | Significant Unintended Edits |
Drug | Clinical Trials | Sponsor | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Progeria | LMNA | ABEmax | Split-intein dual-AAV9 in mouse LMNA, in vivo | 30–55% | 15% bystander | n/a | n/a | n/a | [122] |
| Hypercholesterolemia | Pcsk9 | ABE8.8 | LNP in monkey, in vivo | 66% | Low | VERVE-101, VERVE-102 | NCT05398029, NCT06164730 | Verve Therapeutics | [123] |
| Hypercholesterolemia | Pcsk9 | ABEmax | LNP in monkey, in vivo | 34% | Low | n/a | n/a | n/a | [124] |
| Hypercholesterolemia | Pcsk9 | v3em PE3 | Split-intein dual-AAV9 in mouse, in vivo | 39% | Low on-target indels, no off-target | n/a | n/a | n/a | [50] |
| Hypercholesterolemia | Pcsk9 | ZFP-EvoETR, dCas9-EvoETR |
LNP in mouse, in vivo | 75% reduction | Limited off-target repression | n/a | n/a | n/a | [125] |
| Hypercholesterolemia | Angptl3 | SpCas9 nuclease | LNP in mouse C57BL/6, in vivo | 39% | None | n/a | n/a | n/a | [126] |
| Transthyretin amyloidosis | Ttr | SpCas9 nuclease | LNP in mouse and rat Ttr, in vivo | 70% | None | NTLA-2001 | NCT04601051, NCT05697861 | Intellia Therapeutics | [127] |
| Tyrosinemia | Fah | ABE6.3 | Hydrodynamic injection in mouse Fahmut/mut, in vivo | 10% | 2% bystander, no off-target | n/a | n/a | n/a | [128] |
| Tyrosinemia | Fah | PE2 | Hydrodynamic injection in mouse Fahmut/mut, in vivo | 7% | None | n/a | n/a | n/a | [91] |
| Tyrosinemia | Fah | split PE (sPE) | Dual-AAV8 in mouse Fahmut/mut, in vivo | 1.3% | n/a | n/a | n/a | n/a | [129] |
| Tyrosinemia | Fah | ABEmax and ABE8e | Electroporation in mouse HT1 CdHs, ex vivo | 2.4% and 9.2% | 29% and 11% bystander, no off-target | n/a | n/a | n/a | [130] |
| Tyrosinemia | Fah | PE3b | Electroporation in mouse HT1 CdHs, ex vivo | 2.3% | None | n/a | n/a | n/a | [130] |
| Tyrosinemia | Fah | PE-Cas9-based deletion and repair (PEDAR) | Hydrodynamic injection in mouse FahΔExon5, in vivo | 0.8% | 9.6% and 0.1% on-target indels | n/a | n/a | n/a | [131] |
| Alpha-1 antitrypsin deficiency (AATD) | SERPINA1 | Cas9 nuclease (HDR) | AAV8 and AAV9 in mouse PiZ, in vivo | 2% | 22% on-target indels, no off-target | n/a | n/a | n/a | [132] |
| AATD | SERPINA1 | Cas9 nuclease (+/−HDR) | AAV8 in mouse PiZ, in vivo | 98% reduction in mutant AAT | n/a | n/a | n/a | n/a | [133] |
| AATD | SERPINA1 | CBE and ABE | LNP in mouse PiZ, in vivo | 27% and 36% | 2% bystander, no off-target DNA, off-target RNA not looked | n/a | n/a | n/a | [134] |
| AATD | AATD | PE2 and PE* | Hydrodynamic injection in mouse PiZ, in vivo | 10–15% | n/a | n/a | n/a | n/a | [135] |
| AATD | AATD | PE2 | Split-intein AAV8 in mouse PiZ, in vivo | 3% | n/a | n/a | n/a | n/a | [135] |
| Phenylketonuria (PKU) | Pah | PE2ΔRnH | AdV in mouse Pahenu2, in vivo | 11% | None | n/a | n/a | n/a | [136] |
| Primary hyperoxaluria type 1 (PH1) | Agxt/Hao1 | SaCas9 nuclease | AAV8 in mouse Agxt1−/−, in vivo | 80% | None | n/a | n/a | n/a | [137] |
| PH1 | Agxt/Hao1 | SaCas9 nuclease | Dual AAV8 in mouse Agxt1−/−, in vivo | 55% | n/a | n/a | n/a | n/a | [138] |
| PH1 | Agxt/Hao1 | D10ASaCas9n | Dual AAV8 in mouse Agxt1−/−, in vivo | 57% | None | n/a | n/a | n/a | [139] |
| Hereditary angioedema (HAE) | KLKB1 | Cas9 nuclease | LNP in mouse huKLKB1 and monkey, in vivo | 70% | n/a | NTLA-2002 | NCT05120830 | Intellia Therapeutics | [140] |
PE* = nuclear localization signal sequence optimized PE2.