Table 4 Pioneering preclinical studies on AAV-based gene therapies for treating spinal muscular atrophy (SMA)
Treatment | Mouse model | Survival time (days) | SMN level | Motor function | Physiology | Refs. | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Target | AAV type | Route | Dose (vg) | Treatment day(s) | Body weight | Spinal MN | NMJ morphology | Myofiber size | |||||
Protein-coding genes | |||||||||||||
 UBA1 (E1 ubiquitin-like modifier activating enzyme 1) | scAAV9 | i.v. | 2.4 × 1011 | P0 | Taiwanese mice | 9– > 12 |  +  |  +  |  +  |  +  |  +  |  +  | [57] |
 TMEM41B (Stasimon; STAS) | scAAV9 | i.c.v. | 1 × 1011 | P0 | SMNΔ7 | – | − |  +  | − |  +  | − | na | [61] |
 PLS3 (Plastin 3) | AAV9 | i.c.m. | 1 × 1010 | P1 | SMNΔ7 | 11– > 17 | − | na | na | na | na | na | [65] |
 PLS3 | scAAV9 | i.v. | 1 × 1011 | P1 | Smn2B/– | 30– > 43 | − | na | - | na | na | na | [66] |
|  |  |  |  |  | SMNΔ7 | – | − | na | na | na | na | na |  |
 PLS3 w/morpholino ASO |  |  |  |  | SMNΔ7 | 30– > 44 |  +  |  +  |  +  | na |  +  |  +  |  |
 SNCA (Alpha Synuclein) | scAAV9 | i.c.v. | 1 × 1011 | P1 | Smn2B/– | – | na | na | − | na | na | na | [67] |
|  |  |  | 3 × 1011 | P1 | Smn2B/– | 26– > 49 | na | na |  +  | na |  +  | na |  |
 STMN1 (Stathmin) | scAAV9 | i.c.v. | 1 × 1011 | P2 | Smn2B/– | 20– > 30 | − |  +  |  +  |  +  |  +  | na | [72] |
 DOK7 (Downstream of tyrosine kinases 7) | scAAV9 | i.v. | 1 × 1011 | P1 | Smn2B/– | 21– > 22 | − |  +  | − | − |  +  |  +  | [82] |
Small non-coding RNAs | |||||||||||||
 miR-23a | scAAV9 | i.v. | 1 × 1011 | P1 | Smn2B/– | 20– > 35 | − | na | − |  +  |  +  |  +  | [87] |
 miR-34a | scAAV9 | i.v. | 1 × 1010 | P1 | SMNΔ7 | – | na |  +  | na | na |  +  | na | [88] |
 siPTEN | scAAV6 | i.m. | 1 × 1010 | P1 | SMNΔ7 | na | na | na | na | na |  +  | na | [91] |
|  | scAAV9 | i.v. | 1 × 1010 | P1 | SMNΔ7 | 10– > 30 | − |  +  |  +  |  +  | na | na |  |
 ExSpeU1 (Exon-specifically engineered U1 snRNA) | AAV9 | i.p. | 1.5 × 1012 | P0 + P2 | Taiwanese mice | 10– > 219 |  +  |  +  |  +  | na | na | na | [93] |
Gene editing | |||||||||||||
 Adenine base editor (ABE; ABE8e-SpyMac) | AAV9 | i.c.v. | 2.7 × 1013 vg/kg body weight | P0 | SMNΔ7 | 17– > 22 |  +  | na | na | na | na | na | [154] |
 ABE w/nusinersen |  |  |  |  | SMNΔ7 | (17– >) 29– > 77 |  +  |  +  |  +  | na | na | na |  |
 SMN1 homology-independent targeted integration (SMN1-HITI) | AAV-PHP.eB | i.v. | 1 × 1011 | P0.5 | SMNΔ7 | Male: 15– > 18.5; female: 15– > 17 | na |  +  |  +  | na | na | na | [156] |
 SMN1-HITI w/ SMN1 cDNA |  |  |  |  |  | Male: 72.5– > 182; female: 176– > 220 |  +  |  +  |  +  | na | na | na |  |