Table 2.
Gene therapies for NDD + E
| Disease | Therapy and vector | Delivery | Outcomes | Reference | Major hurdles to gene therapy |
|---|---|---|---|---|---|
| Rett syndrome | MECP2 (AAV9) | Tail vein IV injection, ICV injection | Increased survival and improved behavioural phenotypes. | Gadalla et al., 2013 | Over‐supplementation can cause NDD. Mosaicism makes supplementation difficult to target. |
| MECP2 (AAV9) | Tail vein injection, intracranial injection | Increased survival and improved behavioural phenotypes. | Garg et al., 2013 | ||
| Instability‐prone MECP2 (AAV‐PHP.eb) | Tail vein IV injection | Increased survival and improved behavioural phenotypes. | Luoni et al., 2020 | ||
| Fragile X syndrome | Fmr1 (AAV5 with AAV2 ITR) | IH injection | Rescued hippocampal deficits. | Zeier et al., 2009 | Over‐supplementation can cause NDD. Mosaicism makes supplementation difficult to target. |
| Fmr1 (AAV9) | ICV injection | Improved limited behavioural phenotypes. | Golizadeh, et al. 2014 | ||
| Angelman syndrome | Cas9 targeting mGluR5 (Gold nanoparticles) | Intracranial injection | Reduced repetitive behaviours | Lee, Guenther, et al., 2018 |
Over‐supplementation can cause NDD. Over‐supplementation can cause NDD. Mosaicism makes supplementation difficult to target. |
| UBE3A (AAV9) | IH injection | Improved seizure, ataxia and growth phenotypes. | Daily et al., 2011 | ||
| Tuberous sclerosis complex | Ube3a‐ATS antisense oligonucleotide | IC and IH injection | Improved associative learning. | Meng et al., 2015 |
Precise TSC over‐expression should be pursued. Gene supplementation should ideally target TSC1 or TSC2deficient cells. |
| TSC1 (AAVRH8) | ICV injection | Increased survival and improved motor phenotype and brain pathology | Prabhakar et al., 2015 | ||
| CDKL5‐deficiency disorder | TSC1 (AAVRH8 and AAV9) | ICV injection and IV injection | Increased survival at P0 and P21 and improved motor phenotype and brain pathology | Prabhakar et al., 2019 | Mosaicism makes gene supplementation difficult to target. |
| CDKL5‐deficiency disorder | CDKL5 (AAV‐PHP.B) | Intrajugular injection | Improved limited behavioural phenotypes. | Gao et al., 2020 | Mosaicism makes gene supplementation difficult to target. |
|
DNM1 encephalopathy Dravet syndrome |
Anti‐Dnm1 miRNA (AAV9) | ICV injection | Improved seizure, ataxia and growth phenotypes. | Aimiuwu et al., 2020 |
Gene silencing needs to be pathogenic allele‐specific. SCN1A is larger than the AAV packaging limit. Supplementation needs to specifically target interneurons |
| Anti‐Scn1a antagoNAT | Lumbar intrathecal injection | Improved seizure phenotype. | Hsiao et al., 2016 | ||
| Scn1b (AAV9) | ICV and intracisterna magna injection | Sexually divergent rescue of limited phenotypes. | Niibori et al., 2020 | ||
| CRISPRa targeting Scn1a (dual AAV9) | ICV injection | Improved febrile seizure phenotype. | Colasante, Qiu, et al., 2020 | ||
| SCN8A encephalopathy | Anti‐Scn8a antisense oligonucleotide | ICV injection | Improved survival and delayed seizure onset | Lenk et al., 2020 | SCN8A is larger than the AAV packaging limit |
CDKL5, Cyclin‐dependent kinase‐like 5; IC, infantile convulsions; ICV, intracerebroventricular; IH, intrahippocampal; MECP2, methyl‐CpG binding protein 2; NDD, neurodevelopmental disorders with epilepsy