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. 2021 Apr 20;11(4):611. doi: 10.3390/biom11040611

Table 4.

Selection of the most relevant pre-clinical studies on CNS-directed gene therapy in animal models of LSDs using AAV vectors (vg: vector genomes; gc: genome content, equivalent of vg; vp: viral particles; iu: infective units; pu: purified units; P: Post-natal day; E: Embryonic day; NHP: non-human primate).

Delivery Route Disease Species Model Vector Dose Time of injection Ref.
Intraparenchymal (IC)
CLN1 Batten Mouse C57BL/6-Ptt1−/− AAV9-CAG-hPTT1 1 × 1012 vg/mL P1 [191]
CLN2 Batten Mouse C57BL/6-CLN2−/− AAV2 or AAV5-CAG-hCLN2 3.6 × 109 gc 6 or 10 weeks [192]
CLN2 Batten Mouse C57BL/6:129Sv-TPPI−/− AAV2 or AAV5-CAG-hCLN2 1.2–3.6 × 109 gc 6 or 10 weeks [192]
CLN3 Batten Mouse C57BL/6N-Cln3Δex7/8 AAVrh10-CAG-hCLN3 3 × 1010 gc P2 [193]
Gaucher Mouse GBAL444P/L444P AVV5-CAG-hGBA 3.5 × 1013 vg/mL 8 months [194]
GM1 Mouse C57BL/6-βgal−/− AAV1-CAG-mβgal 4 × 1010 gc 6–8 weeks [195]
GM2 (Sandhoff) Mouse C57BL/6-Hexb−/− AAV1-HEXA and AAV1-HEXB 9.9 × 109 and 1.4 × 1010 gc 1 month [196]
Krabbe Mouse C57BL/6-twiW339X or C57BL/129SVJ/FVB/N-twi-trs AAV1-CMV-mGALC 3 × 1010 vp P0–P1 [197]
Krabbe Mouse B6.CE-Galctwi/J AAV2 or AAV5-CAG-GALC 5.5 × 106 iu P3 [198]
MLD Mouse C57BL/6J-ASA−/− AAVrh10-CAG-hARSA or AAV5-PGK-hARSA 2.3 × 109 vg 8 and 16 months [199]
MPS I Mouse C57BL/6-Idua−/− AAV2 or AAV5-PGK-hIDUA 109 vg 6–7 weeks [200]
MPS I Mouse C57BL/6-Idua−/− AAV2 or AVA5-mPGK-hIDUA 109 vg 6–7 weeks [200]
MPS IIIA Mouse C57BL/6-Sgsh−/− AAVrh10-PGK-SGSH-IRES-SUMF1 7.5 × 109 gc 5 weeks [201]
MPS IIIA Mouse C57BL/6-Sgsh−/− AAVrh10-CMV-SGSH-IRES-SUMF1 7.5 × 109 gc 5 weeks [201]
MPS IIIA Mouse C57BL/6-Sgsh−/− AAVrh10-CAG-hSGSH 8.4 × 108, 4.1 × 1010, 9 × 1010 vg 5–6 weeks [202]
MPS IIIB Mouse C57BL/6-Naglu−/− AAV2 or AAV5-mPGK-hNAGLU 109 vg 6 weeks [203]
MPS IIIB Mouse C57BL/6-Naglu−/− AAV5-CAG-hNAGLU 1.8 × 1010 vp P2–4 [204]
MPS IIIC Mouse Hgsnat−/− AAV2TT-CAG-hcoHGSNAT 5.2 × 109 vg 8 weeks [205]
MPS VII Mouse B6.C-H-2bm1/byBirgusmps/+ AAV5-RSV-GUSB 3 × 109 vg 6–8 weeks [206]
MPS VII Mouse C3H/HeOuJ-Gusbmps-2J AAV1, AAV9 or AAVrh10-GUSB-hGUSB 1.2–1.3 × 1010 vg >2 months [207]
NP-A Mouse C57BL/6-ASMKO−/− AVV2-CMV-hASM 1.86 × 1010 gc 10 weeks [208]
GM1 Cat fGM1 AAV1 or AAVrh8-CAG-fβgal 3 × 1011, 4 × 1012 or 1.2 × 1013 vg 1.3–3 months [209]
GM2 (Sandhoff) Cat fGM2 AAV1-CAG-fHEXA/B or AAV8-DC172-HEXA/B 3 × 1011–3.2 × 1012 vg 0.9–2.6 months [210]
GM2 (Sandhoff) Cat fGM2 AAVrh8-CAG-HEXA, AAVrh8-CAG-HEXB 1.6–4.5 × 1011 vg 1 month [211]
MPS I Dog IDUA −/− AAV5-PGK-hIDUA 5 × 1011–2.1 × 1012 vg 18–30 months [212]
MPS IIIB Dog Schipperke Naglu−/− AAV5-PGK-hNAGLU 5 × 1011–2.1 × 1012 vg 18–30 months [212]
CLN2 Batten Rat Fisher 344 AAV2-CAG-TPP1 109–1010 pu NA [213]
CLN2 Batten NHP C. sabaeus AAV2-CAG-TPP1 3.6 × 1011 pu 5–10 years [213]
Intrathecal (IT)
Krabbe Mouse B6.CE-Galctwi/J AAV9, AAVrh10 or AAVOlig001-CAGGS-mβgal 2 × 1011 vg P10–11 [214]
MPS I Mouse C57BL/6-IDUA−/− AAV2-CMV-hIDUA 2 × 109–4 × 1010 vp 2–4 months [215]
MPS VII Mouse Gusb −/− AAV2-CMV-mGUSB 1 × 1011 and 5 × 1011 vp P3 and 7–13 weeks [216]
GM1 Cat βgal −/− AAVrh10-βgal 1 × 1012 vg/kg NA [217]
MPS I Cat IDUA −/− AVV9-IDUA 1 × 1012 gc/kg NA [218]
Cisterna Magna (CM)
MPS IIIA Mouse C57BL/6-SGSHD31N AAV9-CAG-mSgsh 5 × 109–5 × 1010 vg 2 months [219]
MPS IIIB Mouse C57BL/6-Naglu−/− AVV9-CAG-mNaglu 3 × 1010 vg 2 months [220]
MPS IIID Mouse C57BL/6NTac-Gnstm1e(EUCOMM)Hmgu AAV9-CAG-mGns 5 × 1010 vg 2 months [221]
Pompe Mouse 6neo/6neo AAV9 or AAVrh10-CAG-hGAA 1011 vg 1 month [222]
AMD Cat MANB −/− AAV1-GUSB-fMANB 1 × 1013 gc 4–6 weeks [223]
GM1 Cat βgal −/− AAVrh10-βgal 1 × 1012 vg/kg NA [217]
MPS I Cat IDUA −/− AAV9-CB-fIDUA, AAV9-CMV-fIDUA 1012 gc/kg 4–7 months [224]
MPS I Dog IDUA −/− AAV9-CAG-IDUA 1012 gc/kg 1 month [225]
MPS I Dog IDUA −/− AAV9-CAG-IDUA 1011–1012 gc/kg 1 month [226]
MPS VII Dog GUSB −/− AAV9 or AAVrh10-CAG-caGUSB 5 × 1012 gc/kg 3 weeks [227]
Intracerebroventricular (ICV)
CLN6 Batten Mouse Cln6 nclf AAV9-CMV-hCLN6 5 × 1010–5 × 1011 vg P0 [228]
CLN8 Batten Mouse C57BL/6J-Cln8 mnd AAV9.pT-MecP2.CLN8 5 × 1010 vg P0–P1 [229]
Gaucher Mouse CD1-K14-ln/ln AAV9-GUSB-hGBA1 5 × 1010 gc E16 and P0 [146]
GM1 Mouse βgal −/− AAV1-CAG-mβgal 3.2 × 109 vg P0 [230]
Krabbe Mouse C57BL/6-twiW339X or C57BL/129SVJ/FVB/N-twi-trs AAV1-CMV-mGALC 3 × 1010 vp P0–P1 [197]
MLD Mouse C57BL/6J-Asratm1Gie AAV1-CAG-ARSA 2 × 1011 vg 8–12 weeks [231]
MLD Mouse C57BL/6J-Asratm1Gie AAV1, 9-CAG-ARSA 1.1 × 1011–2.3 × 1011 vg 8 and 18 weeks [232]
MPS I Mouse C57BL/6-IDUA−/− AAV8-CAG-hIDUA 2 × 1010 vg P4-P6 [233]
MPS I Mouse C57BL/6-IDUAnull AAV5-CBA-hIDUA 1 × 1011 vp 8–11 weeks [234]
MPS IIIA Mouse B6Cg-Sgsh(mps3/PstJ) AAV5-CMV-SGSH-IRES-SUMF1 6 × 109–3 × 1010 vp P0 [235]
MPS III A Mouse B6Cg-Sgsh(mps3a/PstJ) AAV9-CMV-IDSspSGSH-IRES-SUMF1 5.4 × 1012 gc/kg P60 [236]
MPS VII Mouse C3H/HeOuJ-Gusbmps-2J AVV1, 2, 5-GUSB-GUSB 1.8 × 1010 vg P0 [237]
MPS VII Mouse B6.C-H-2bm1/byBirgusmps/+ AAV4-RSV-hGUSB 1 × 1010 vg 6–8 weeks [238]
MSD Mouse C57B6/S129J-Sumf−/− AAV4, 9-CMV-SUMF1 1.2 × 1010 vg P1 [152]
NP-C Mouse BALB/cNctr-Npc1m1N/J AAV9-hSYN-hNPC1 4.6 × 109 vg P0 [239]
GM1 Cat βgal −/− AAVrh10-βgal 1 × 1012 vg/kg NA [217]
CLN2 Batten Dog Dachshunds TPP1null AAV2-CAG-caTPP1 1.6 × 107 vg 3 months [240]
CLN5 Batten Sheep CLN5 −/− AAV9-CBh-CLN5 4 × 1012 vg 2–3 months [241]
Combination
IC + IT CLN1 Batten Mouse C57BL/6-Ptt1−/− AAV9-CAG-hPTT1 1 × 1012 vg/ml P1 [191]
IC + ICV GM2 (Sandhoff) Cat fGM2 AAVrh8-CAG-HEXA/B 1.1 × 1012 vg 1.1–1.6 months [242]
IC + ICV GM2 (Sandhoff) Cat fGM2 AAVrh8-CAG-HEXA, AAVrh8-CAG-HEXB IC: 1.6–4.5 × 1011 vg; ICV: 6.4 × 1011 vg 1 month [211]
CM + ICV CLN2 Batten Dog Dachshunds TPP1null AAV2-CAG-caTPP1 1.6 × 107 vg 3 months [240]
IC + ICV CLN5 Batten Sheep CLN5 −/− AAV9-CBh-CLN5 3.1 × 1012 vg 2–3 months [241]
IC + ICV GM2 (Tay-Sachs) Sheep TSD AAVrh8-CAG-HEXA, AAVrh8-CAG-HEXA/B 6.3 × 1012 vg, 4.2 × 1012–1.3 × 1013 vg 2–4 months [243]