Gene Therapy for Neurodevelopmental Disorders


Neurodevelopmental disorders (NDDs) are a heterogeneous group of devastating conditions characterised by impairments of the central nervous system early during course of development and maturation. Although common NDDs tend to have complex aetiology, other major NDDs are inherited disorders with a known single‐gene or chromosomal abnormality. Effective treatments are rare for these diseases. The most critical challenges in therapeutic development are the broad, complex neuropathology and circumventing the blood–brain barrier. Gene therapy has been a promising approach for treating NDDs, especially monogenic disorders. With recent progress in understanding the disease mechanisms, and improvements to gene delivery vectors and strategies, the clinical potential of gene therapy for NDDs is being realised. This is particularly true for the neuropathic lysosomal storage diseases, in which multiple promising vector administration approaches are under development.

Key Concepts:

  • Gene therapy provides therapeutics by delivery of targeted genes.

  • Monogenic NDDs are good candidates for gene therapies that target the root causes.

  • Neuropathology of NDDs is usually broad or global in the CNS.

  • The blood–brain barrier poses a major challenge for CNS gene delivery.

  • Adeno‐associated virus serotype 9 vector has the ability to cross the blood–brain barrier.

Keywords: neurodevelopmental diseases (NDDs); CNS gene delivery; viral vectors; adeno‐associated virus; blood–brain barrier (BBB)


Auerbach BD, Osterweil EK and Bear MF (2011) Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480(7375): 63–68.

Baek RC, Broekman ML, Leroy SG et al. (2010) AAV‐mediated gene delivery in adult GM1‐gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS One 5(10): e13468.

Bankiewicz KS, Forsayeth J, Eberling JL et al. (2006) Long‐term clinical improvement in MPTP‐lesioned primates after gene therapy with AAV‐hAADC. Molecular Therapy 14(4): 564–570.

Bevan AK, Duque S, Foust KD et al. (2011) Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Molecular Therapy 19(11): 1971–1980.

Biffi A, Capotondo A, Fasano S et al. (2006) Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. Journal of Clinical Investigation 116(11): 3070–3082.

Boelens JJ, Prasad VK, Tolar J, Wynn RF and Peters C (2010) Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatric Clinics of North America 57(1): 123–145.

Boulet SL, Boyle CA and Schieve LA (2009) Health care use and health and functional impact of developmental disabilities among US children, 1997–2005. Archives of Pediatrics and Adolescent Medicine 163(1): 19–26.

Boutin S, Monteilhet V, Veron P et al. (2010) Prevalence of serum IgG and neutralizing factors against adeno‐associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Human Gene Therapy 21(6): 704–712.

Calcedo R, Morizono H, Wang L et al. (2011) Adeno‐associated virus antibody profiles in newborns, children, and adolescents. Clinical and Vaccine Immunology 18(9): 1586–1588.

Cartier N, Hacein‐Bey‐Abina S, Bartholomae CC et al. (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X‐linked adrenoleukodystrophy. Science 326(5954): 818–823.

Cartier N, Hacein‐Bey‐Abina S, Bartholomae CC et al. (2012) Lentiviral hematopoietic cell gene therapy for X‐linked adrenoleukodystrophy. Methods in Enzymology 507: 187–198.

Cearley CN and Wolfe JH (2006) Transduction characteristics of adeno‐associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Molecular Therapy 13(3): 528–537.

Cearley CN and Wolfe JH (2007) A single injection of an adeno‐associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. Journal of Neuroscience 27(37): 9928–9940.

Chen YH, Claflin K, Geoghegan JC and Davidson BL (2012) Sialic acid deposition impairs the utility of AAV9, but not peptide‐modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease. Molecular Therapy 20(7): 1393–1399.

Deane R and Zlokovic BV (2007) Role of the blood‐brain barrier in the pathogenesis of Alzheimer's disease. Current Alzheimer Research 4(2): 191–197.

Desmaris N, Verot L, Puech JP et al. (2004) Prevention of neuropathology in the mouse model of Hurler syndrome. Annals of Neurology 56(1): 68–76.

Desnick RJ and Schuchman EH (2012) Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annual Review of Genomics and Human Genetics 13: 307–335.

Dominguez E, Marais T, Chatauret N et al. (2011) Intravenous scAAV9 delivery of a codon‐optimized SMN1 sequence rescues SMA mice. Human Molecular Genetics 20(4): 681–693.

Duque S, Joussemet B, Riviere C et al. (2009) Intravenous administration of self‐complementary AAV9 enables transgene delivery to adult motor neurons. Molecular Therapy 17(7): 1187–1196.

Ellinwood NM, Ausseil J, Desmaris N et al. (2011) Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes. Molecular Therapy 19(2): 251–259.

Foust KD, Nurre E, Montgomery CL et al. (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nature Biotechnology 27(1): 59–65.

Foust KD, Wang X, McGovern VL et al. (2010) Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nature Biotechnology 28(3): 271–274.

Fraldi A, Hemsley K, Crawley A et al. (2007) Functional correction of CNS lesions in an MPS‐IIIA mouse model by intracerebral AAV‐mediated delivery of sulfamidase and SUMF1 genes. Human Molecular Genetics 16(22): 2693–2702.

Fratantoni JC, Hall CW and Neufeld EF (1968) Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 162(853): 570–572.

Fu H, DiRosario J, Kang L, Muenzer J and McCarty DM (2010) Restoration of central nervous system alpha‐N‐acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno‐associated viral type 2 vector delivery. Journal of Gene Medicine 12(7): 624–633.

Fu H, DiRosario J, Killedar S, Zaraspe K and McCarty DM (2011) Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans‐blood–brain barrier gene delivery. Molecular Therapy 19(6): 1025–1033.

Fu H, Muenzer J, Samulski RJ et al. (2003) Self‐complementary adeno‐associated virus serotype 2 vector: global distribution and broad dispersion of AAV‐mediated transgene expression in mouse brain. Molecular Therapy 8(6): 911–917.

Fu H, Samulski RJ, McCown TJ et al. (2002) Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno‐associated virus‐mediated gene delivery. Molecular Therapy 5(1): 42–49.

Gadalla KK, Bailey ME, Spike RC et al. (2013) Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Molecular Therapy 21(1): 18–30.

Gao G, Vandenberghe LH and Wilson JM (2005) New recombinant serotypes of AAV vectors. Current Gene Therapy 5(3): 285–297.

Garbuzova‐Davis S, Louis MK, Haller EM et al. (2011) Blood–brain barrier impairment in an animal model of MPS III B. PLoS One 6(3): e16601.

Gentner B, Visigalli I, Hiramatsu H et al. (2010) Identification of hematopoietic stem cell‐specific miRNAs enables gene therapy of globoid cell leukodystrophy. Science Translational Medicine 2(58): 58ra84.

Glascock JJ, Osman EY, Wetz MJ et al. (2012a) Decreasing disease severity in symptomatic, Smn(−/−);SMN2(+/+), spinal muscular atrophy mice following scAAV9‐SMN delivery. Human Gene Therapy 23(3): 330–335.

Glascock JJ, Shababi M, Wetz MJ, Krogman MM and Lorson CL (2012b) Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy. Biochemical and Biophysical Research Communications 417(1): 376–381.

Gray SJ, Matagne V, Bachaboina L et al. (2011) Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Molecular Therapy 19(6): 1058–1069.

Gray SJ, Woodard KT and Samulski RJ (2010) Viral vectors and delivery strategies for CNS gene therapy. Therapeutic Delivery 1(4): 517–534.

Hartung SD, Frandsen JL, Pan D et al. (2004) Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno‐associated virus vector transducing the human alpha‐L‐iduronidase gene. Molecular Therapy 9(6): 866–875.

Haurigot V, Marco S, Ribera A et al. (2013) Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. Journal of Clinical Investigation 123(8): 3254–3271.

Jeyakumar M, Thomas R, Elliot‐Smith E et al. (2003) Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126(Pt 4): 974–987.

Langford‐Smith A, Wilkinson FL, Langford‐Smith KJ et al. (2012) Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Molecular Therapy 20(8): 1610–1621.

Leone P, Janson CG, Bilaniuk L et al. (2000) Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Annals of Neurology 48(1): 27–38.

Leone P, Shera D, McPhee SW et al. (2012) Long‐term follow‐up after gene therapy for canavan disease. Science Translational Medicine 4(165): 165ra163.

Liu JY, Thom M, Catarino CB et al. (2012) Neuropathology of the blood–brain barrier and pharmaco‐resistance in human epilepsy. Brain 135(10): 3115–3133.

McCarty DM, DiRosario J, Gulaid K, Muenzer J and Fu H (2009) Mannitol‐facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice. Gene Therapy 16(11): 1340–1352.

McIntyre C, Byers S and Anson DS (2010) Correction of mucopolysaccharidosis type IIIA somatic and central nervous system pathology by lentiviral‐mediated gene transfer. Journal of Gene Medicine 12(9): 717–728.

McPhee SW, Francis J, Janson CG et al. (2005) Effects of AAV‐2‐mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. Brain Research Molecular Brain Research 135(1–2): 112–121.

Mussche S, Devreese B, Nagabhushan Kalburgi S et al. (2013) Restoration of cytoskeleton homeostasis after gigaxonin gene transfer for giant axonal neuropathy. Human Gene Therapy 24(2): 209–219.

Neufeld EF and Muenzer J (2001) The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease, 8th edn, pp. 3421–3452. New York; St Louis; San Francisco: McGraw‐Hill.

Pardridge WM (2002) Drug and gene delivery to the brain: the vascular route. Neuron 36(4): 555–558.

Piguet F, Sondhi D, Piraud M et al. (2012) Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Human Gene Therapy 23(8): 903–914.

Ruzo A, Marco S, Garcia M et al. (2012) Correction of pathological accumulation of glycosaminoglycans in central nervous system and peripheral tissues of MPSIIIA mice through systemic AAV9 gene transfer. Human Gene Therapy 23(12): 1237–1246.

Samulski RJ, Berns KI, Tan M and Muzyczka N (1982) Cloning of adeno‐associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proceedings of the National Academy of Sciences of the USA 79(6): 2077–2081.

Sands MS and Barker JE (1999) Percutaneous intravenous injection in neonatal mice. Laboratory Animal Science 49(3): 328–330.

Sands MS and Haskins ME (2008) CNS‐directed gene therapy for lysosomal storage diseases. Acta Paediatrica Supplement 97(457): 22–27.

Sargeant TJ, Wang S, Bradley J et al. (2011) Adeno‐associated virus‐mediated expression of beta‐hexosaminidase prevents neuronal loss in the Sandhoff mouse brain. Human Molecular Genetics 20(22): 4371–4380.

Schendel D, Rice C and Cunniff C (2010) The contribution of rare diseases to understanding the epidemiology of neurodevelopmental disabilities. In: Posada de la Paz M and Groft SC (eds) Rare Diseases Epidemiology, Advances in Experimental Medicine and Biology, chap. 34, pp. 433–453. London, New York: Springer Science.

Sferra TJ, Qu G, McNeely D et al. (2000) Recombinant adeno‐associated virus‐mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis type VII mouse. Human Gene Therapy 11(4): 507–519.

Shimizu F and Kanda T (2013) Disruption of the blood‐brain barrier in inflammatory neurological diseases. Brain and Nerve 65(2): 165–176.

Song SK, Lee SK, Lee JJ et al. (2011) Blood–brain barrier impairment is functionally correlated with clinical severity in patients of multiple system atrophy. Neurobiology of Aging 32(12): 2183–2189.

Valori CF, Ning K, Wyles M et al. (2010) Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Science Translational Medicine 2(35): 35ra42.

Visigalli I, Delai S, Politi LS et al. (2010) Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 116(24): 5130–5139.

Wang D, El‐Amouri SS, Dai M et al. (2013) Engineering a lysosomal enzyme with a derivative of receptor‐binding domain of apoE enables delivery across the blood‐brain barrier. Proceedings of the National Academy of Sciences of the USA 110(8): 2999–3004.

Wang D, Zhang W, Kalfa TA et al. (2009) Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross‐correction in mice with Hurler syndrome. Proceedings of the National Academy of Sciences of the USA 106(47): 19958–19963.

Watson G, Bastacky J, Belichenko P et al. (2006) Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Therapy 13(11): 917–925.

Weinberg MS and McCown TJ (2013) Current prospects and challenges for epilepsy gene therapy. Experimental Neurology 244: 27–35.

Worgall S, Sondhi D, Hackett NR et al. (2008) Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno‐associated virus expressing CLN2 cDNA. Human Gene Therapy 19(5): 463–474.

Zeier Z, Kumar A, Bodhinathan K et al. (2009) Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Therapy 16(9): 1122–1129.

Zhang H, Yang B, Mu X et al. (2011) Several rAAV vectors efficiently cross the blood–brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Molecular Therapy 19(8): 1440–1448.

Zheng Y, Ryazantsev S, Ohmi K et al. (2004) Retrovirally transduced bone marrow has a therapeutic effect on brain in the mouse model of mucopolysaccharidosis IIIB. Molecular Genetics and Metabolism 82(4): 286–295.

Zincarelli C, Soltys S, Rengo G and Rabinowitz JE (2008) Analysis of AAV serotypes 1‐9 mediated gene expression and tropism in mice after systemic injection. Molecular Therapy 16(6): 1073–1080.

Further Reading

Abbott NJ (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery. Journal of Inherited Metabolic Disease 36(3): 437–449.

Berns KI and Giraud C (1996) Biology of adeno‐associated virus. Current Topics in Microbiology and Immunology 218: 1–23.

Byrne BJ, Falk DJ, Clement N and Mah CS (2012) Gene therapy approaches for lysosomal storage disease: next‐generation treatment. Human Gene Therapy 23(8): 808–815.

Pardridge WM (2010) Biopharmaceutical drug targeting to the brain. Journal of Drug Targeting 18(3): 157–167.

Simonato M, Bennett J, Boulis NM et al. (2013) Progress in gene therapy for neurological disorders. Nature Reviews Neurology 9(5): 277–291.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
McCarty, Douglas M, and Fu, Haiyan(Apr 2014) Gene Therapy for Neurodevelopmental Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025276]