Table 1 Summary of the preclinical studies discussed in this review

Barth syndrome

Suzuki-Hatano et al. (2019). Hum Gene Ther [23]

AAV9

1 × 10¹³ vg/kg

P1(IV)

3 months (IV)

Symptom improvement

Wang et al. (2020). Circ Res [25]

AAV9

1 × 10¹³ vg/kg

2 × 10¹³ vg/kg

P1 (SubQ)

20 days (RO)

2 months (RO)

Neonatal administration rescued neonatal death, prevented development of cardiac phenotype. Adult administration prevented or reversed cardiac dysfunction

Friedreich ataxia

Perdomini et al. (2014). Nat Med [36]

AAVrh10**

5.4 × 10¹³ vg/kg

3 weeks (IV)

Pre-symptomatic administration prevents phenotype development. Post-symptomatic treatment reversed disease

Piguet et al. (2018). Mol Ther [39]

AAV9

5 × 10¹³ vg/kg

1 × 10¹⁰ vg × 3 (brain)

3.5 weeks (IV)

7.5 weeks (IV/IC)

IV only partially improved phenotype. IV and IC treatment resulted in symptom improvement

Gerard et al. (2014). Mol Ther Methods Clin Dev [41]

AAV9

6 × 10⁹ to 6 × 10¹¹ vg

5–9 days (IP)

Increased survival and reduced symptoms

Leigh syndrome

Di Meo et al. (2017). Gene Ther [49]

AAV9

1 × 10¹², 2 × 10¹² vg

1.5 × 10¹¹, 3 × 10¹¹ vg

P1 (IV/ICV)

The combination of IV and ICV treatment improved survival and reduced symptoms. IV or ICV alone did not increase survival or improve symptoms

Reynaud-Dulaurier et al. (2020). Brain [50]

PHP.B

1 × 10¹² vg

1 month (IV)

Increased survival and delayed disease progression

Silva-Pinheiro et al. (2020). Mol Ther Methods Clin Dev [51]

PHP.B

1 × 10¹²vg, 2 × 10¹² vg

26 or 28 days (IV)

Increased survival and delayed disease progression

Pereira et al. (2020). EMBO Mol. Med [54]

AAV9

1.25 × 10¹⁵ vg/kg (juveniles)

1.66 × 10¹⁵ vg/kg (adults)

15–8 days (RO)

2 months (RO)

Treatment of juveniles prevents development of disease. Treatment of adults corrected established disease

Ling et al. (2021) Mol Ther [58]

scAAV9

8 × 10¹¹ vg, 2 × 10¹¹ vg, 8x¹¹vg + 8x¹¹vg (IV + IT)

4 weeks (IT or IV + IT)

Increased CIV activity in brain, muscle, and liver

Decreased blood lactate following exhaustive exercise

Ethylmalonic encephalopathy

Di Meo et al. (2012). EMBO Mol Med.[71]

AAV8

4 × 10¹³ vg/kg

21 days (IV)

Increased survival and improved motor function

MNGIE

Torres-Torronteras et al. (2018). Hum Gene Ther.[85]

AAV8

2 × 10¹¹, 1 × 10¹², 2 × 10¹² vg/kg

8–12 weeks (IV)

Sustained lowering of plasma dThd and dUrd levels

Cabrera-Perez et al. (2019). Hum Gene Ther. [86]

AAV8

5 × 10¹⁰, 2 × 10¹¹, 5 × 10¹¹ vg/kg (TBG)

5 × 10¹⁰, 2 × 10¹¹, 5 × 10¹¹, 10¹², 2 × 10¹² vg/kg (AAT)

2 × 10¹¹, 5 × 10¹¹, 1 × 10¹², 2 × 10¹² vg/kg (PGK, HLP)

8–12 weeks (IV)

Sustained lowering of plasma dThd levels. Liver-specific promoters resulted in the longest supression of dThd levels

Vila-Julia et al. (2020). EBioMed [88]

AAV8

5 × 10¹¹, 1 × 10¹², 2 × 10¹², 1 × 10¹³ vg/kg (TBG)

2 × 10¹², 1 × 10¹³ vg/kg (AAT, HLP)

8–11 weeks (IV)

Sustained lowering of plasma dThd and dUrd levels, modestly improved motor performance, and modestly decreased ventricular volume

MPV17

Bottani et al. (2014). Mol Ther.[90]

AAV8

4 × 10¹², 4 × 10¹³ vg/kg

2 months (IV)

Treatment after beginning ketogenic diet improved liver phenotype. Treatment prior to ketogenic diet prevented further liver damage

TK2 deficiency

Lopez-Gomez et al. (2021). Ann Neurol [101]

AAV9, AAV2

2.1 × 1011, 4.2 × 1011

P1 (RO)

Improved survival and motor function

SLC25a46

Yang et al. (2020). Hum Mol Gen [108]

AAV-PHP.eB

1 × 10¹¹, 2 × 10¹⁴ vg/kg

P2 (IV)

Improved survival, development of less severe phenotype

Leber hereditary optic neuropathy

Yu et al. (2012). Proc Natl Acad Sci USA [119]

MTS-AAV2

1 × 10⁸ vg (intravitreal)

N/A***

Pre-treatment protected against vision loss

Yu et al. (2018). Sci Rep.[122]

MTS-AAV2

4.4 × 10⁸ vg

3 months (intravitreal)

Stably improved visual function