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. 2020 Apr 15;7:57. doi: 10.3389/fmolb.2020.00057

TABLE 1.

List of LSDs having neurodegeneration and currently available pre-clinical mouse models.

Gene Disease Mouse model Neurodegeneration Recaps clinical phenotype Pre-clinical trial use
Mucopolysaccharidosis
IDUA Mucopolysaccharidosis, type I Idua(–/–) (Clarke et al., 1997) + + AAV (Hartung et al., 1999, 2004; Desmaris et al., 2004), BMT (Kuehn et al., 2015; Pievani et al., 2015), Crispr (Miki et al., 2019), ERT (Tong et al., 2017; Le et al., 2018; Ghosh et al., 2019), HSCT (Watson et al., 2014; Azario et al., 2017), LV (Di Domenico et al., 2005), NVGT (Aronovich et al., 2007, 2009; Osborn et al., 2008, 2011), RV (Chung et al., 2007)
Idua(–/–) (Ohmi et al., 2003) + + AAV (Watson et al., 2006; Janson et al., 2014; Ou et al., 2019), BMT (Nan et al., 2012; Wolf et al., 2012), Crispr (Schuh et al., 2018), ERT (Piller Puicher et al., 2012; Pasqualim et al., 2015; Lizzi Lagranha et al., 2017), LV (Wang et al., 2009; da Silva et al., 2012; Ou et al., 2016), NVGT (Camassola et al., 2005; Stilhano et al., 2015), RV (Zheng et al., 2003; Baldo et al., 2013), ZFN (Ou et al., 2019)
Idua(W392X) (Wang et al., 2012) + + Crispr (Wang et al., 2018), ERT (Baldo et al., 2012) NST (Wang et al., 2012; Keeling et al., 2013)
Idua(–/–) (Mendez et al., 2015) + + BT (Azario et al., 2017), HSCT (Gomez-Ospina et al., 2019)
IDS Mucopolysaccharidosis type II Ids(–/–) (Muenzer et al., 2002) + + AAV (Cardone et al., 2006; Polito and Cosma, 2009; Motas et al., 2016), ERT (Muenzer et al., 2002; Polito et al., 2010), NVGT (Friso et al., 2008), ZFN (Laoharawee et al., 2018)
Ids(–/–) (Jung et al., 2010) + + AAV (Jung et al., 2010), ERT (Lee et al., 2011, 2014; Higuchi et al., 2012; Hong et al., 2012; Sohn et al., 2018)
SGSH Mucopolysaccharidosis, type IIIA Mgat3(–/–) (Bhaumik et al., 1999) + + AAV (Fraldi et al., 2007; Haurigot et al., 2013), AI (Arfi et al., 2011), BMT (Lau et al., 2012), LV (McIntyre et al., 2008), SRT (Roberts et al., 2010)
Mgat3(D31N) (Bhattacharyya et al., 2001) + + AAV (Ruzo et al., 2012; Haurigot et al., 2013), ERT (Gustavsson et al., 2019), GT (Quiviger et al., 2014), SRT (Roberts et al., 2007)
Mgat3(CKO) (Lau et al., 2017) +* <*
NAGLU Mucopolysaccharidosis, type IIIB Naglu (–/–) (Li et al., 1999) + + AAV (Cressant et al., 2004; Ribera et al., 2015), ERT (Kan et al., 2014), LV (Di Natale et al., 2005)
HGSNAT Mucopolysaccharidosis, type IIIC Hgsnat (–/–) (Martins et al., 2015) + + AAV (Tordo et al., 2018)
Hgsnat (–/–) (Marcó et al., 2016) + + AAV (Marcó et al., 2016)
GNS Mucopolysaccharidosis, type IIID Gns (–/–) (Roca et al., 2017) + + AAV (Roca et al., 2017)
Glycoproteinoses
MAN2B1 Alpha-Mannosidosis Man2b1(–/–) (Stinchi et al., 1999) + + ERT (Roces et al., 2004; Blanz et al., 2008; Damme et al., 2011)
NEU1 Sialidosis, Type I & II Neu1(–/–) (de Geest et al., 2002) + <
Neu1(V54M) (Bonten et al., 2013) + + Chaperone-AAV (Bonten et al., 2013)
Sphingolipidoses
ASAH1 Farber disease Asah1P361R (Alayoubi et al., 2013) + + LV (Alayoubi et al., 2013)
Asah1(–/–) (Eliyahu et al., 2012) Embryonic lethal −
ASA Metachromatic leukodystrophy Asa (–/–) (Hess et al., 1996) + < AI (Stein et al., 2015), ERT (Matzner et al., 2005; Matthes et al., 2012), HSCT (Biffi et al., 2004; Capotondo et al., 2012), OLP (Givogri et al., 2006), RV (Matzner et al., 2000)
GALC Krabbe disease GalcTwi (Kobayashi et al., 1980) + + AAV (Lin et al., 2015; Rafi et al., 2015a), AI (Luzi et al., 2009), AO (Hawkins-Salsbury et al., 2012), BMT (Luzi et al., 2005), Combination (Qin et al., 2012; Hawkins-Salsbury et al., 2015; Ricca et al., 2015), HSCT (Yeager et al., 1984, 1991; Yagi et al., 2004), Nerve Graft (Scaravilli and Jacobs, 1981, 1982; Scaravilli and Suzuki, 1983)
Galctwi–5J (Potter et al., 2013) + +
Galc(H168C) (Luzi et al., 2001) + +
Galc(G270D) (Matthes et al., 2015) + + ERT (Matthes et al., 2015)
Sapa(–/–) (Matsuda et al., 2001) + + HSCT (Yagi et al., 2005)
GBA Gaucher disease, type II Gba(–/–) (Tybulewicz et al., 1992) - -
Gba(L444P) (Liu et al., 1998) - -
Gba(pmuts) (Xu et al., 2003) + +
Gba(lnl/lnl) (Enquist et al., 2007) + + Chaperone (Dasgupta et al., 2015), CM (Liou et al., 2016), ERT (Cabrera-Salazar et al., 2010), SRT (Cabrera-Salazar et al., 2012)
GLB1 GM1-Gangliosidosis Glb1(–/–) (Matsuda et al., 1997) + + Chaperone (Takamura et al., 2011)
Glb1(–/–) (Hahn et al., 1997) + < BMT (Sano et al., 2005), SRT (Kasperzyk et al., 2005; Elliot-Smith et al., 2008)
HEXA GM2-gangliosidosis, type I HexA(–/–) (Sango et al., 1995) - -
HexA(–/–) (Yamanaka et al., 1994) - - SRT (Platt et al., 1997)
HexA(–/–) & Neu3(–/–) (Seyrantepe et al., 2018) + +
HEXB GM2-gangliosidosis, type II HexB(–/–) (Sango et al., 1995) + + AAV (Sargeant et al., 2011; Cachon-Gonzalez et al., 2014), BMT (Norflus et al., 1998; Wada et al., 2000), CM (Pelled et al., 2003), Diet (Denny et al., 2010), HSP (Kirkegaard et al., 2016), MIP-1 (Wu and Proia, 2004), SRT (Jeyakumar et al., 1999)
HexB(–/–) (Sargeant et al., 2011) + +
NPC1 Niemann-pick disease, type C1 Npc1(–/–) (Morris et al., 1977) + - AAV (Chandler et al., 2017b; Xie et al., 2017; Hughes et al., 2018), AI (Alvarez et al., 2008), AO (Fu et al., 2013), CM (Erickson et al., 2000; Repa et al., 2007; Abi-Mosleh et al., 2009; Liu et al., 2010; Taylor et al., 2012; Hovakimyan et al., 2013; Nusca et al., 2014; Tanaka et al., 2014; Soga et al., 2015; Demais et al., 2016), Diet (Jelinek et al., 2015; Soga et al., 2015), HSP (Chung et al., 2016; Kirkegaard et al., 2016), NS (Griffin et al., 2004; Liao et al., 2009), Transplant (Veyron et al., 1996)
Npc1(D1005G) (Maue et al., 2012) + + HSP (Chung et al., 2016)
Npc1(Flox) (Elrick et al., 2010) +** <**
Npc1(P202A & F203A) (Xie et al., 2011) + +
Npc1(I1061T) (Praggastis et al., 2015) + <
Npc1(1554–1004G<A) (Gómez-Grau et al., 2017) + +
SMPD1 Niemann-pick disease, type A & B Asm(–/–) (Otterbach and Stoffel, 1995) + +
Asm(–/–) (Horinouchi et al., 1995) + + AAV (Passini et al., 2007), NSMA (Arroyo et al., 2014), ERT (Dodge et al., 2009)
Lysosomal transport defects
CTN5 Cystinosis Ctns(–/–) (Cherqui et al., 2002) + < ERT (Cherqui et al., 2002; Simpson et al., 2011), HSCT (Syres et al., 2009; Rocca et al., 2015; Gaide Chevronnay et al., 2016)
SLC17A5 Free sialic acid storage disorder Sialin(–/–) (Prolo et al., 2009) + +
Multiple enzyme deficiency
SUMF1 Multiple sulfatase deficiency Sumf1(–/–) (Settembre et al., 2007) + + AAV (Spampanato et al., 2011)
GNPTAB Mucolipidosis, type II Gnptab(–/–) (Ko et al., 2016) + + AAV (Ko et al., 2016)
Gnptab(Y888) (Paton et al., 2014) + +
Gnptab(–/–) (Gelfman et al., 2007) + <
MCOLN1 Mucolipidosis, type IV Mcoln1(–/–) (Venugopal et al., 2007) + + BMT (Walker and Montell, 2016), SRT (Boudewyn et al., 2017)
Glycogen storage disease
GAA Glycogen storage disease Gaa(–/–) (Raben et al., 1998) + + AAV (Rucker et al., 2004; Zhu et al., 2005; Gatto et al., 2017; Puzzo et al., 2017), BMT (Mori et al., 2008), Chaperone (Khanna et al., 2012, 2014), ERT (Raben et al., 2001, 2002, 2010; Xu et al., 2004), SRT (Ashe et al., 2010; Douillard-Guilloux et al., 2010)
Gaa(–/–) (Bijvoet et al., 1998) + + HSCT (van Til et al., 2010)
LAMP2 Danon disease Lamp2(y/–)*** (Tanaka et al., 2000) + +
Neuronal ceroid lipofuscinosis
CLN2 Ceroid lipofuscinosis, neuronal 2 Cln2(–/–) (Sleat et al., 2004) + + AAV (Sondhi et al., 2008; Chen et al., 2009), Anti-Apoptosis (Kim et al., 2009), ERT (Kim et al., 2008; Sleat et al., 2008; Meng et al., 2012)
CLN3 Ceroid lipofuscinosis, neuronal 3 Cln3 (–/–) (Cotman et al., 2002) + + AI (Dannhausen et al., 2018)
Cln3(LacZ) (Eliason et al., 2007) + + Membrane Fluidity Modulation (Schultz et al., 2018)
Cln3 (–/–) (Mitchison et al., 1999) + + AMPARA (Kovacs and Pearce, 2008), CaM (Chang et al., 2007)
CLN6 Ceroid lipofuscinosis, neuronal 6 Cln6(–/–) (Bronson et al., 1998) + + Diet (Mirza et al., 2013), LV (Jankowiak et al., 2015)
PPT1 Ceroid lipofuscinosis, neuronal 1 Ppt1(–/–) (Gupta et al., 2001) + + AAV (Macauley et al., 2014; Shyng et al., 2017), AO (Wei et al., 2011; Saha et al., 2012), ERT (Hu et al., 2012), NMDARA (Finn et al., 2013), SRT (Sarkar et al., 2013)
Ppt1(R151X) (Miller et al., 2015) + + NST (Miller et al., 2015)
Ppt1(C451T) (Bouchelion et al., 2014) + +

AAV, Adeno-associated virus; AI, Anti-Inflammatory; AMPARA, AMPA-Receptor antagonist; AO, Anti-Oxidant; BMT, Bone Marrow Transplant; BT, Blood Transfusion; CaM, Ca2+ Modulation; CM, Cholesterol Modulation; ERT, Enzyme Replacement Therapy; HSCT, Hematopoietic Stem Cell Transplant; HSP, Heat shock protein; LV, Lentivirus; NMDARA, NMDA-Receptor Antagonist; NSMA, Neutral Sphingomyelinase Activation; NS, Neurosteroids; NST, Nonsense Suppression Therapy; NVGT, Non-Viral Gene Transfer; OLP, Oligodendrocyte Progenitor Therapy; RV, Retrovirus; SRT, Substrate Reduction Therapy; ZFN, Zinc Finger Nuclease. (+) distinguishes murine models of LSD that presents neuronal degeneration or presents with analogous disease progression as seen in humans. (−) a lack of neuronal degeneration and/or comparable disease pathology. (<) Represents murine models that display a similar yet milder disease progression than human patients. *The neuronal degeneration and recaps clinical phenotype designations for the Mgat3(CKO) model were interpreted from the conditional knockout mice model crossed to with CMV-Cre line; a model with ubiquitous expression across all tissue types. **The neuronal degeneration and recaps clinical phenotype designations for the NPC1(Flox) model were interpreted from the conditional knockout mice crossed with Pcp2-Cre line; a driver targeting most Purkinje cells and some retinal bipolar neurons. ***The Lamp2 gene resides on the X chromosome of mouse genome, therefore; the investigators used hemizygous null males designated as Lamp2(y/–).