Table 1.
Clinical trials of rAAV-based gene therapies for neurodegenerative diseases.
| Therapeutic | Specificity | Trial Benchmarks | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Disease 1 | Gene (Name) |
Protein Function and Therapeutic Rationale | Mechanism/Approach | Delivery | Serotype | Promoter 2 | Cumulative Duration | Most Advanced Phase | Sponsor | Trial ID 3 |
| AD | APOE2 (LX1001) |
Apolipoprotein E ε2 is an isoform of APOE that is reduced in neurons in AD and confers protection. |
EGE/AE | Cisterna magna | AAVrh.10h | CAG | 2019–2023 | I | Lexeo Therapeutics | NCT05400330 |
| hTERT (AAV-hTERT) |
Human telomerase reverse transcriptase elongates chromosomal ends in dividing cells. hTERT activity is reduced in neurons in AD. |
EGE/AE | Intravenous and intrathecal | unknown | unknown | 2019–2021 | unknown | Libella Gene Therapeutics |
NCT04133649 | |
| NGF (CERE-110) |
Nerve growth factor promotes the growth and development of sympathetic and parasympathetic neurons. NGF activity is reduced in neurons in AD. | EGE/AE | Nucleus basalis of Meynert | AAV2 | CAG | 2004–2015 | II | Sangamo | NCT00876863 | |
| BDNF (AAV2-BDNF) |
Brain-derived neurotrophic factor promotes the development and maintenance of neuronal populations. BDNF activity is reduced in AD neurons. |
EGE/AE | Intraparenchymal | AAV2 | unknown | 2021–2025 | Recruiting | Mark Tuszynski | NCT05040217 | |
| PD | AADC (AAV- hAADC-2) |
Aromatic L-amino acid decarboxylase contributes to the biosynthesis of dopamine. There is a progressive loss of dopaminergic neurons expressing AADC in PD. |
EGE/AE | Putamen | AAV2 | CMV | 2013–2022 | II | Voyager Ther, Neurocr. Biosci | NCT00229736 |
| GAD (AAV-GAD) |
Glutamic acid decarboxylase plays a role in the biosynthesis of GABA. Progressive loss of GABAergic neurons expressing GAD reduces motor inhibition in PD. |
EGE/AE | Subthalamic nucleus |
AAV2 | CBA | 2003–2005 | I | Neurologix | NCT05603312 | |
| GDNF (AAV2-GDNF) |
Glial cell-derived neurotrophic factor promotes the survival of neurons. There is a progressive loss of nigrostriatal dopaminergic neurons expressing GDNF in PD. | EGE/AE | Putamen | AAV2 | unknown | 2013–2022 | I | Ask Bio, NINDS |
NCT04167540 | |
| NRTN (CERE-120) |
Neurturin is a neurotrophic factor that promotes the survival of neuronal populations. There is a progressive loss of dopaminergic neurons expressing NRTN in PD. | EGE/AE | Putamen | AAV2 | CAG | 2005–2017 | II | Sangamo | NCT00252850 | |
| GBA1 (LY3884961) |
Glucocerebrosidase plays a role in the biosynthesis of glucose and ceramide. Aberrant mutations in GBA1 in dopaminergic neurons occur in PD. | EGE/AE | Cisterna magna | AAV9 | CBA | 2020–2027 | I/II | Prevail Therapeutics | NCT04127578 | |
| FTD | GRN (PBFT02) |
Granulin promotes the growth, survival, and maintenance of neuronal and microglial populations. GRN activity is reduced in neurons in FTD. | EGE/AE | Cisterna magna | AAV1, AAV9 | unknown | 2020–2027 | I/II | Passage Bio, Prevail Therapeutics | NCT04747431 |
| HD | HTT (rAAV5-miHTT) |
Huntington is a cytosolic protein that regulates neuronal and glial function. There are aberrant ≥36 CAG repeats in the HTT gene in HD. | EGR using miRNA/AE | Intrastriatal | AAV5 | unknown | 2019–2026 | I/II | UniQure Biopharma | NCT04120493 |
| SMA | SMN (AVXS-101) |
Survival motor neuron is a neurotrophic factor that promotes the maintenance of motor neurons. SMN activity is reduced in motor neurons in SMA. |
EGE/AE | Intravenous and intrathecal | AAV9 | CBA | 2014–2035 | IV | Novartis Gene Therapy |
NCT02122952 |
1 FTD, frontotemporal dementia; HD, Huntington’s Disease; SMA, spinal muscular atrophy; EGE, exogenous gene expression; EGR = exogenous gene repression; AE, augmented expression; SE, supressed expression. 2 Note that CBA and CAG are alternative acronyms for the same promoter. In assembling this table, we presented the information on promoters as they were provided by the respective study authors. 3 For additional details regarding these trials, see clinicaltrials.gov. In instances when multiple clinical trials have been associated with a gene therapy, only the Trial ID for the most recent trial is shown.