Table 1.
Summary of current body-wide and central nervous system (CNS)-targeted adeno-associated virus (AAV)-mediated gene replacement therapy clinical trials for neuromuscular diseases, as reported in ClinicalTrials.gov.
| PRODUCT/ADMINISTRATION | CLINICAL DESIGN | SERIOUS ADVERSE EVENTS | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| DISEASE | AAV Serotype | Promoter | Transgene | Name | Administration/Dose | Clinical Trial ID (Study Name) Sponsor/Collaborator | Study Phase/Status | Study Timelines (Clinical Follow-Up) | Age, Gender, Actual or Estimated/ Planned Number of Participants Enrolled |
|
| DMD | AAV9 | CK8 | Micro-dystrophin | SGT-001 | Intravenous 2 doses |
NCT03368742 (IGNITE DMD) Solid Biosciences, LLC | Phase ½ active, not recruiting | 2017–2024 (2 years) | 4 to 17 years, males, n = 16/same as current | Complement activation kidney failure, platelet count drop (n = 1 at 5 × 1013 vg/kg) + cardiopulmonary insufficiency (n = 1 at 2 × 1014 vg/kg) [185,186] |
| DMD | AAVrh74 | MHCK7 | Micro-dystrophin | SRP-9001 | Intravenous 2 × 1014 vg/kg |
NCT03375164 Sarepta Therapeutics, Inc. | Phase ½ active, not recruiting | 2018–2021 (3 years) | 3 months to 7 years, males, n = 4/12 |
No serious adverse events [177] |
| DMD | AAVrh74 | MHCK7 | Micro-dystrophin | SRP-9001 | Intravenous 1 dose |
NCT03769116 Sarepta Therapeutics, Inc. | Phase 2 active, not recruiting | 2018–2026 (5 years) | 4 years to 7 years, males, n = 41/24 | - |
| DMD | AAV9 | Human muscle-specific | Mini-dystrophin | PF-06939926 | Intravenous 1 × 1014 vg/kg 3 × 1014 vk/kg |
NCT03362502 Pfizer | Phase 1B active, not recruiting | 2018–2026 (5 years) | 4 years and older, males, n = 30/12 | Antibody response, complement activation, acute kidney injury, haemolysis, thrombocytopenia (n = 1 at 3 × 1014 vg/kg) [187] |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intravenous 6.7 × 1013 vg/kg 2 × 1014 vg/kg |
NCT02122952 AveXis, Inc. | Phase 1 completed | 2014–2017 (2 years) | Up to 6 months of age, males and female, n = 15/9 | Elevated serum aminotransferase levels (˃10× normal level) [44] |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intravenous therapeutic dose |
NCT03306277 (STR1VE) AveXis, Inc. | Phase 3 completed | 2017–2019 (18 months of age) | Up to 6 months of age, males and females, n = 22/15 | - |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intrathecal 6 × 1013 vg 1.2 × 1014 vg 2.4 × 1014 vg |
NCT03381729 (STRONG) AveXis, Inc. | Phase 1 suspended (on clinical hold pending further discussions regarding pre-clinical findings) | 2017–2021 (15 months) | 6 to 60 months of age, males and females, n = 51/27 | SAE mainly related to the disease itself (n = 7). Transaminitis events probably related to treatment (n = 2). [188] |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intravenous | NCT03461289 (STRIVE-EU) AveXis, Inc. | Phase 3 completed | 2018–2020 (18 months of age) | Up to 6 months of age, males and females, n = 33/30 | - |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intravenous 1.1 × 1014 vg/kg |
NCT03505099 (SPR1NT) AveXis, Inc./PRA Health Sciences | Phase 3 active, not recruiting | 2018–2021 (18 and 24 months of age) | Up to 42 days, males and females, n = 30/44 | - |
| SMA | AAV9 | Hybrid CMV enhancer/chicken β-actin promoter | Human SMN | AVXS-101 | Intravenous single dose |
NCT03837184 AveXis, Inc./PRA Health Sciences | Phase 3 active, not recruiting | 2019–2021 (18 months of age) | Up to 6 months of age, males and females, n = 2/6 | - |
| XLMTM | AAV8 | Des | Human MTM1 | AT132 | Intravenous 1 × 1014 vg/kg 3 × 1014 vg/kg |
NCT03199469 (ASPIRO) Audentes Therapeutics | Phase ½ active, not recruiting (FDA placed on clinical hold since June 2020) | 2017–2024 (5 years) | Up to 5 years, males, n = 24/12 | Progressive liver dysfunction, hyperbilirubinemia, death from sepsis or gastrointestinal bleeding (n = 3/17 at 3 × 1014 vg/kg) [189] |
| Pompe | AAV2/8 | Liver-specific promoter | hGAA | ACTUS-101 | Intravenous 2 doses |
NCT03533673 Asklepios Biopharmaceuticals, INC./Duke University and National Institute of Arthritis and Musculoskelatal and Skin Diseases (NIAMS) | Phase ½ recruiting | 2018–2022 (52 weeks) | 18 years and older, males and females, n = 8/6 | - |
| Pompe | AAV | Liver-specific promoter | hGAA | SPK-3006 | Intravenous dose escalation |
NCT04093349 (RESOLUTE) Spark Therapeutics | Phase ½ Recruiting | 2020–2023 (52 weeks) | 18 years and older, males and females, n = 20/same as current | - |
| Pompe | AAV8 | Hybrid liver/desmin promoter | hGAA | AT845 | Intravenous 2 doses |
NCT04174105 (FORTIS) Audentes Therapeutics | Phase ½ Recruiting | 2020–2027 (5 years) | 18 to 80 years, males and females, n = 8/same as current | - |
| Danon | AAV9 | CAG | hLAMP2B | RP-A501 | Intravenous 2 doses |
NCT03882437 Rocket Pharmaceuticals Inc. | Phase 1 recruiting | 2019–2023 (3 years) | 8 years to 14 years and 15 years and older, males, n = 24/same as current |
- |
| LGMD2E | scAAV rh74 |
MHCK7 | SGCB | SRP-9003 | Intravenous 5 × 1013 vg/kg |
NCT03652259 Sarepta Therapeutics, Inc. | Phase ½ active, not recruiting | 2018–2020 (3 years) | 4 to 15 years, males and females, n = 6/9 |
Elevated liver enzymes associated with transient increase in bilirubin (n = 1) [190] |
| Batten disease | AAV2 | CU | hCLN2 | - | CNS administration 3 × 1012 vg |
NCT00151216 Weill Medical College of Cornell University/Nathan’s Battle Foundation | Phase 1 completed | 2004–2019 (18 months) | 3 to 18 years, males and females, n = 10/11 |
- |
| Batten disease | AAVrh.10 | CU | hCLN2 | - | Direct CNS administration 9 × 1011 vg/2.85 × 1011 vg |
NCT01414985 Weill Medical College of Cornell University | Phase ½ completed | 2010–2017 (18 months) | 3 to 18 years, males and females, n = 8/16 |
- |
| Batten disease | AAVrh.10 | CU | hCLN2 | - | Direct CNS administration 9 × 1011 vg 2.85 × 1011 vg |
NCT01161576 Weill Medical College of Cornell University/National Institute of Health | Phase 1 active, not recruiting | 2010–2032 (18 months) | 2 to 18 years, males and females, n = 25/16 |
- |
| Batten disease | scAAV9 | CB | CLN6 | AT-GTX-501 | Intrathecal | NCT02725580 Amicus Therapeutics | Phase 1/2A active, not recruiting | 2016–2021 (24 months) | 1 year and older, males and females, n = 13/6 | - |
| Batten disease | scAAV9 | P546 | CLN3 | AT-GTX-502 | Intrathecal 2 doses |
NCT03770572 Amicus Therapeutics | Phase 1/2A active, not recruiting | 2018–2023 (36 months) | 3 to 10 years, males and females, n = 7/same as current |
- |
| GSD1a | AAV8 | Native promoter | G6Pase | DTX401 | Intravenous 3 doses |
NCT03517085 Ultragenyx Pharmaceutical INC | Phase 1/2 recruiting | 2018–2020 (52 weeks) | 18 years and older, males and females, n = 18/9 | No treatment-related serious adverse events reported to date |
DMD: Duchenne muscular dystrophy; SMA: Spinal muscular atrophy; XLMTM: X-linked myotubular myopathy; LGMD2E: Limb girdle muscular dystrophy type 2E; GSD1a: Glycogen storage disease type 1a.