. 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	Asah1^P361R (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	Galc^Twi (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)
		Galc^twi–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/–).