Table 1.
Overview of liver gene therapy reported preclinical studies and clinical trials.
| Gene Addition | ||
|---|---|---|
| Preclinical Studies | Clinical Trials | |
| Hemophilia A * | AAV2-cFVIII, AAV6-cFVIII and AAV8-cFVIII, mice and dogs [13]; BMN 270 (AAV5-hFVIII-SQ, valoctocogene roxaparvovec), mice and nonhuman primates (NHPs) [14]. |
NCT02576795 funded by BioMarin Pharmaceutical (AAV5-hFVIII-SQ) [15]; NCT03003533 funded by Spark Therapeutics (novel AAV) [16]; Valoctocogene Roxaparvovec, phase 3 in 134 male patients [17]. |
| Hemophilia B ** | Several pre-clinical studies were performed. In mice, e.g., [18]; in dogs, e.g., [19]; and in nonhuman primates, e.g., [20]. | Several studies in small groups of adult patients were performed. The first trial (NCT00076557) resulted in a transient correction [7]. Upon showing efficacy of transient immune suppression in a second trial (NCT03369444), long-term correction was obtained, Nathwani et al., 2011 [8]. Additional studies have further optimized the effect, e.g., by using the factor IX Padua mutant with higher activity. For a complete overview, see Muczynski et al., 2024 [21]. |
| Crigler–Najjar Syndrome | Several preclinical studies were performed in rats, e.g., [22], and in mice, e.g., [23]. | The first trial (NCT03223194) only included a single patient and resulted in a transient correction. The second trial NCT03466463 treating 5 adult female patients did show sustained correction when using the higher dose, D’Antiga et al., 2023 [24]. |
| OTCD | Several AAV serotypes (2, 7, 8 and 9 resp.) expressing OTC were studied in mice, showing prolonged correction in adult animal, [25], but transient correction in neonatal mice [26,27]. In primates, an AAV8 (DTX301) vector was tested in macaques [28], and an AAV vector with a modified capsid, AAVLKO3.hOTC, was tested in juvenile cynomolgus monkeys [29]. AAV2/8-hOTC-CO was tested in mice [30]. |
scAAV8OTC, phase 1–2, ongoing [31] Atrial using an Ad5vector NCT00004386 was unsuccessful and was stopped after the death of a patient. A phase 1–2 trial (NCT02991144) using scAAV8-OTC in adults reported correction [32]. A phase 3 trial (NCT05345171) included patients > 12 y. A trial in babies less than 9 months old is ongoing (NCT06255782). |
| GSD-Ia | The liver is used to produce G6PC to overcome enzyme replacement therapy. Firstly in mice [33], then secondly, a similar approach in mice and dogs [34]. | A phase 1–2 trial using AAV8-G6PC was completed (NCT03517085) and, based on results, a phase III trial including patients > 8 y is now ongoing (NCT05139316). |
| Mucopolysaccharidosis, different diseases | In mice, e.g., Watson et al., 1998 [35], reporting correction and Cardone et al., 2006 [36]; in cats, e.g., Cotugno et al., 2011 [37]; in NHPs, e.g., Hordeaux et al., 2019 [38]. | Many in vivo strategies using AAV6, AAV8, AAV9, and AAVrh10 vectors [39]. |
| AIP | Mouse model for porphobilinogen deaminase (PBGD)-deficiency rAAV2/5- hPBGD, mice [40]; rAAV5-cohPBGD, safety and efficacy in macaques [41]. |
rAAV2/5- PBGD, phase 1 in 8 patients (NCT02082860) [42]. |
| AATD | To correct liver deficiency and the tox of the misfolded enzyme, a combination was used: knock-down misfolded form and expression of the correct form in mice, Li et al. [43]; miRNA and gene addition, Mueller et al. [44]; Most clinical trials targeted muscle, because the mutated allele causes liver damage, efficacy of gene editing to disrupt this allele is investigated [45,46]. |
rAAV2-CB-hAAT, phase 1, (NCT01054339) [47] muscle targeted; rAAV2-AAT, phase 1 in 12 patients, (NCT00377416) [48] muscle targeted, safe but not effective; rAAV1-CB-hAAT, phase 2 in 9 patients, (NCT00430768) [49] muscle targeted; recent trial targeting liver (NCT02168686) (AAVrh10), no data reported; good candidate for gene editing. Maybe combined with gene addition. Fazirsiran to reduce misfolded enzyme [50]. |
| Wilson disease | AAV8-TTR-hATP7Bco, mice [51]. | AAVx-ATP7B, phase 1, ongoing (NCT04884815). |
| HoFH | AAV2-TBG-hLDLR, AAV2/7-TBG-hLDLR, AAV2/8-TBG-hLDLR, mice [52]; AAV8.TBG.mLDLR, AAV8.TBG.hLDLR, mice [53]; AAV8.IVS2.hLDLR011-T, mice [54]; AAV8.TBG.hLDLR, macaques [55]. |
AAV8-hLDLR, phase 1–2 in 9 patients (NCT02651675). Results not reported but discontinued. Another phase 1 trial (NCT06125847) is ongoing. |
| PFIC3 | AAV8-hABCB4, mice [56]; AAV-MDR3-Aco, mice [57]; AAV8-MDR3, mice [58]. |
N.A. |
* Hemophilia A: Roctavian®, the AAV5 SQ product was approved by EMA [59] in 2022 and approved by FDA in 2023 [60]. ** Hemophilia B: Hemgenix®, AAV5, factor IX-Padua was approved by EMA in 2023 [61] and approved by FDA in 2022 [62]. OTCD, ornithine transcarbamylase deficiency; GSD-Ia, glycogen storage disease type Ia; AIP, acute intermittent porphyria; AATD, alpha 1-antitrypsin deficiency; HoFH, homozygous familial hypercholesterolemia; PFIC3, progressive familial intrahepatic cholestasis type 3.