A review of animal models utilized in preclinical studies of approved gene therapy products: trends and insights

Soufizadeh, Parham; Mansouri, Vahid; Ahmadbeigi, Naser

doi:10.1186/s42826-024-00195-6

Laboratory Animal Research

Table 3 Animal Models Utilized in Preclinical Studies of Nononcological Products

From: A review of animal models utilized in preclinical studies of approved gene therapy products: trends and insights

Year of Approval	Trade name (General name)	Target cell (in vivo/ex-vivo	Indication	Animal model	Details	Comments	Category	References
2011	Neovasculgen	In vivo	Peripheral vascular disease and limb ischemia	rabbit	N/A	With bone grafting (n = 12) and empty defects (n = 6)	Disease induction	[43]
2012	Glybera	In vivo	Familial Lipoprotein Lipase Deficiency	cat	N/A	Naturally, homozygous for an LPLG412R mutation	Spontaneous	[44, 45]
2012	Glybera	In vivo	Familial Lipoprotein Lipase Deficiency	mice	Immunocompetent	LPL knockout mouse—used for initial studies	Genetically engineered	[44, 45]
2012	Glybera	In vivo	Familial Lipoprotein Lipase Deficiency	mice	Immunocompetent	LPL knockout mouse—further complicated by the presence of significant local muscle pathology	Genetically engineered	[44, 45]
2013	Kynamro	In vivo	Homozygous familial hypercholesterolemia	mice	N/A	Mice bred with no LDL receptor and expressing human apoB-100 who developed extensive atherosclerotic plaques	Genetically engineered	[46]
2016	Ampligen	In vivo	Chronic fatigue syndrome/myalgic encephalomyelitis	N/A	N/A	No information was found for this product	N/A	N/A
2016	Exondys 51	In vivo	Duchenne Muscular Dystrophy (DMD)	mice	mdx	Up to 960 mg/kg/week of IV-administered eteplirsen	genetically engineered	[47]
2016	Exondys 51	In vivo	Duchenne Muscular Dystrophy (DMD)	monkey	N/A	Cubcutaneous or IV administration of eteplirsen up to the 320 mg/kg maximum dose	N/A	[47]
2016	Spinraza	In vivo	Spinal Muscular Atrophy	mice	Δ7	The complete details pertaining to the model are provided within the source	Disease induction	[48]
2016	Spinraza	In vivo	Spinal Muscular Atrophy	mice	Taiwanese type I	The complete details pertaining to the model are provided within the source	Genetically engineered	[48]
2016	Spinraza	In vivo	Spinal Muscular Atrophy	mice	Taiwanese type III	The complete details pertaining to the model are provided within the source	Genetically engineered	[48]
2016	Spinraza	In vivo	Spinal Muscular Atrophy	mice	Burgheron	The complete details pertaining to the model are provided within the source	Genetically engineered	[48]
2016	Strimvelis	Ex-vivo	Severe combined immunodeficiency (SCID) due to ADA deficiency	mice	Immunodeficient	Peripheral blood lymphocytes from patients affected by ADA- SCID were transduced with a retroviral vector for human ADA and injected into immunodeficient mice	Xenograft	[49, 50]
2016	Zalmoxis	Ex-vivo	Restoring the immune system of the patient after hematopoietic stem cell transplantation	mice	Immunodeficient	NOD—Subcutaneously transplanted with human skin	Xenograft	[51]
2017	Invossa	Ex-vivo	Moderate Knee Arthritis	rat	MIA	Monosodium ModoAcetate + Surgery	Disease induction	[52, 53]
2017	Luxturna	In vivo	RPE65 mutation associated retinal dystrophy	dog	N/A	Naturally occurring animal model with mutated RPE65	Spontaneous	[54]
2018	Onpattro	In vivo	Hereditary Transthyretin-related Amyloidosis	mice	hTTR V30M HSF1^±	The complete details pertaining to the model are provided within the source	Genetically engineered	[55]
2018	Tegsedi	In vivo	Hereditary Transthyretin-related Amyloidosis	mice	hTTR-Ile84Ser	The complete details pertaining to the model are provided within the source	Genetically engineered	[56, 57]
2019	Collategene	In vivo	Critical Limb Ischemia	rabbit	N/A	Surgical operation	Disease induction	[58, 59]
2019	Collategene	In vivo	Critical Limb Ischemia	rat	N/A	Surgical operation	Disease induction	[58, 59]
2019	Vyondys 53	In vivo	Duchenne Muscular Dystrophy	mice	mdx/ulmr^ ~ / Xist^^	The complete details pertaining to the model are provided within the source	Genetically engineered	[60, 61]
2019	Waylivra	In vivo	Adult Familial Chylomicronemia syndrome	mice	N/A	C57BL/6 mice, Ldlr -/- mice (B6.129S7-Ldlrtm1Her/J, Jackson Laboratories, Bar Harbor, ME), Ob/Ob (B6. Cg-Lepob/J) and apoC-III -/- mice (B6.129P2 Apoc3tm1Unc)	Disease induction	[62, 63]
2019	Waylivra	In vivo	Adult Familial Chylomicronemia syndrome	mice	CETP Transgenic Ldlr -/- Mice	They were generated by breeding the huCETP Tg animals with mice lacking a functional LDL receptor	Genetically engineered	[62, 63]
2019	Waylivra	In vivo	Adult Familial Chylomicronemia syndrome	monkey	N/A	Administration of a high fructose supplement	Disease induction	[62, 63]
2019	Waylivra	In vivo	Adult Familial Chylomicronemia syndrome	rat	N/A	Sprague Dawley—fed a high fructose diet	Disease induction	[62, 63]
2019	Waylivra	In vivo	Adult Familial Chylomicronemia syndrome	rat	Zucker diabetic	ZDF-Leprfa/Crl—Full information about the model is given in the source	Genetically engineered	[62, 63]
2019	Zolgensma	In vivo	Pediatric Spinal Muscular Atrophy	mice	SMNΔ7	In the SMA mice model (SMNΔ7 mice) a decreased mass of the left ventricle and decreased wall thickness putatively due to eccentric hypertrophy is observed	Genetically engineered	[64, 65]
2019	Zolgensma	In vivo	Pediatric Spinal Muscular Atrophy	monkey	SMA	Injection of scAAV9.CB.GFP in young cynomolgus monkeys	Genetically engineered	[64, 65]
2019	Zynteglo	Ex-vivo	Adult transfusiondependent ß thalassemia	mice	Immunodeficient	BB305 LVV-transduced mouse bone marrow cells (BMCs) immunodeficient, myeloablated mice	Genetically engineered	[66]
2020	Givlaari	In vivo	Porphyria	mice	T1/T2 AIP	Combined PB/DDC inductions were performed in male AIP mice—Full information about the model is given in the source	Genetically engineered	[67,68,69]
2020	Givlaari	In vivo	Porphyria	monkey	N/A	Naive Chinese—Full information about the model is given in the source	N/A	[67,68,69]
2020	Givlaari	In vivo	Porphyria	rat	AIP	PBGD knockdown—Full information about the model is given in the source	Genetically engineered	[67,68,69]
2020	Leqvio	In vivo	Primary hypercholesterolemia	monkey	N/A	Dedicated PD drug interaction studies have not been conducted in animals but the applicant performed a 13-week repeated dose toxicology study in Cynomolgus monkeys with coadministration of inclisiran (once monthly SC) and/or atorvastatin (orally daily)	Disease induction	[70, 71]
2020	Libmeldy	Ex-vivo	Metachromatic Leukodystrophy	mice	As^2–/– MLD	C57BL/6 & congenic C57BL/6 Ly45.1—As^2–/– MLD mice were bred in the H.S. Raffaele animal research facility by intercrossing the homozygous offspring of two carrier mice obtained by rederivation (embryo transfer) of As2–/– males with C57BL/6 females	Spontaneous	[72, 73]
2020	Oxlumo	In vivo	Primary hyperoxaluria type 1	mice	AGT-deficient null	Mutant mice lacking liver AGXTmRNA and protein	Genetically engineered	[74, 75]
2020	Oxlumo	In vivo	Primary hyperoxaluria type 1	monkey	N/A	Naive Chinese	N/A	[74, 75]
2020	Oxlumo	In vivo	Primary hyperoxaluria type 1	rat	N/A	Sprague–Dawley	N/A	[74, 75]
2020	Viltepso	In vivo	Duchenne Muscular Dystrophy	dog	CXMD	With frozen spermatozoa driven from a golden retriever	Spontaneous	[76]
2021	Amondys 45	In vivo	Duchenne Muscular Dystrophy	mice	mdx	The complete details pertaining to the model are provided within the source	Genetically engineered	[77, 78]
2021	Skysona	Ex-vivo	Juvenile Cerebral Adrenoleukodystrophy	mice	Immunodeficient	There are no animal models of CALD that recapitulate the human disease and could be used for demonstration of improvements in cerebral inflammation and demyelination. Brain engraftment of Lenti-D transduced CD34 + HSCs myeloablated immunodeficient mice in pivotal combined in vivo	Genetically engineered	[79, 80]
2022	Hemgenix	In vivo	Hemophilia B	mice	Knock-out	B6.129P2-F9^tm1Dws mouse model of Hemophilia B	Genetically engineered	[81, 82]
2022	Hemgenix	In vivo	Hemophilia B	monkey	N/A	No more information was found for this model	N/A	[81, 82]
2022	Rovtavian	In vivo	Hemophilia A	mice	Immunodeficient	Immune deficient Rag2 constitutive knockout mouse model (B6.129S6-Rag2tm1Fwa N12; Rag2-/-)	Genetically engineered	[83]
2022	Rovtavian	In vivo	Hemophilia A	mice	Immunodeficient	The hemophilia A knockout mouse crossed with a Rag2-/- mouse model (B6;129S-F8tm1Kaz/J x B6.129S6-Rag2tm1Fwa N12; Rag2-/- x FVIII-/-)	Genetically engineered	[83]
2022	Rovtavian	In vivo	Hemophilia A	monkey	N/A	Rhesus—No more information was found for this model	N/A	[83]
2022	Rovtavian	In vivo	Hemophilia A	monkey	N/A	Cynomolgus—No more information was found for this model	N/A	[83]
2022	Upstaza	In vivo	Aromatic L-amino acid decarboxylase (AADC) deficiency	mice	AADC deficiency	AadcS250F/S250F mice carry a conserved C890T base pair (S250F amino acid) mutation in the mouse Ddc gene. This mutation corresponds to a human C835T missense mutation associated with infantile Parkinsonism	Genetically engineered	[84]
2022	Upstaza	In vivo	Aromatic L-amino acid decarboxylase (AADC) deficiency	monkey	N/A	Models of Parkinson’s disease	Genetically engineered	[84]
2022	Upstaza	In vivo	Aromatic L-amino acid decarboxylase (AADC) deficiency	rat	N/A	Models of Parkinson’s disease	Genetically engineered	[84]
2023	Elevidys	In vivo	Duchenne muscular dystrophy	mice	mdx	The complete details pertaining to the model are provided within the source	Genetically engineered	[85]
2023	Elevidys	In vivo	Duchenne muscular dystrophy	rat	Dmd^mdx	The complete details pertaining to the model are provided within the source	Genetically engineered	[86]
2023	Vyjuvek	In vivo	Dystrophic epidermolysis bullosa	mice	Immunodeficient	Colony of homozygous Col7a1flNeo mice, which are a strain expressing only 10% of the amount of murine type VII collagen found in normal mouse skin. For xenografting, NOD/SCID mice were used (NOD.CB17-PrkdcSCID/J mice; stock 001303; The Jackson Laboratory)	Xenograft	[86]

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