Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9.

Several attempts have been made to discover the ideal vector for gene therapy in central nervous system (CNS). Adeno-associated viruses (AAVs) are currently the preferred vehicle since they exhibit stable transgene expression in post-mitotic cells, neuronal tropism, low risk of insertional mutagenesis and diminished immune responses. Additionally, the discovery that a particular serotype, AAV9, bypasses the blood-brain barrier has raised the possibility of intravascular administration as a non-invasive delivery route to achieve widespread CNS gene expression. AAV9 intravenous delivery has already shown promising results for several diseases in animal models, including lysosomal storage disorders and motor neuron diseases, opening the way to the first clinical trial in the field. This review presents an overview of clinical trials for CNS disorders using AAVs and will focus on preclinical studies based on the systemic gene delivery using AAV9.

[1]  E. Ayuso,et al.  Correction of pathological accumulation of glycosaminoglycans in central nervous system and peripheral tissues of MPSIIIA mice through systemic AAV9 gene transfer. , 2012, Human gene therapy.

[2]  Vincent P. Ferrera,et al.  Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task , 2015, PloS one.

[3]  C. Vite,et al.  Adeno-associated virus vector-mediated transduction in the cat brain , 2003, Gene Therapy.

[4]  Michael J. Castle,et al.  Long-distance axonal transport of AAV9 is driven by dynein and kinesin-2 and is trafficked in a highly motile Rab7-positive compartment. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  M. Nonnenmacher,et al.  Intracellular transport of recombinant adeno-associated virus vectors , 2012, Gene Therapy.

[6]  M. Colle,et al.  Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats , 2014, Gene Therapy.

[7]  J. Mendell,et al.  Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[8]  J. Rabinowitz,et al.  Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  D. Lillicrap,et al.  Current status of haemophilia gene therapy , 2014, Haemophilia : the official journal of the World Federation of Hemophilia.

[10]  C. Svendsen,et al.  Delayed Disease Onset and Extended Survival in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex , 2014, The Journal of Neuroscience.

[11]  V. Ferrera,et al.  Noninvasive, Transient and Selective Blood-Brain Barrier Opening in Non-Human Primates In Vivo , 2011, PloS one.

[12]  David V. Schaffer,et al.  Engineering adeno-associated viruses for clinical gene therapy , 2014, Nature Reviews Genetics.

[13]  K. Berns,et al.  Detection of adeno-associated virus (AAV)-specific nucleotide sequences in DNA isolated from latently infected Detroit 6 cells. , 1975, Virology.

[14]  C. Lorson,et al.  Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery. , 2012, Human gene therapy.

[15]  V. Haurigot,et al.  Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy. , 2015, Human molecular genetics.

[16]  K. Messmer,et al.  Reduction of post-traumatic intracranial hypertension by hypertonic/hyperoncotic saline/dextran and hypertonic mannitol. , 1995, Neurosurgery.

[17]  R. Carcenac,et al.  Intramuscular scAAV9-SMN injection mediates widespread gene delivery to the spinal cord and decreases disease severity in SMA mice. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  N. Déglon,et al.  RNA Interference Mitigates Motor and Neuropathological Deficits in a Cerebellar Mouse Model of Machado-Joseph Disease , 2014, PloS one.

[19]  X. Breakefield,et al.  Gene Therapy for the Nervous System: Challenges and New Strategies , 2014, Neurotherapeutics.

[20]  L. Greensmith,et al.  Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model , 2005, Nature Medicine.

[21]  S. Kügler,et al.  Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado-Joseph disease. , 2015, Human molecular genetics.

[22]  R. Samulski,et al.  Integration of adeno-associated virus (AAV) and recombinant AAV vectors. , 2004, Annual review of genetics.

[23]  James M. Wilson,et al.  Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  T. Samulski,et al.  Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors , 1996, Journal of virology.

[25]  D. Schaffer,et al.  Adeno-Associated Virus Vectors and Neurological Gene Therapy , 2015, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[26]  N. Déglon,et al.  Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease , 2008, PloS one.

[27]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[28]  R. Mandel,et al.  AAV9: a potential blood-brain barrier buster. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  Chiou-Miin Wang,et al.  Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain , 2003, Gene Therapy.

[30]  J. Raber,et al.  A role for glia in the progression of Rett’s syndrome , 2011, Nature.

[31]  B. Byrne,et al.  Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[32]  N. Chatauret,et al.  Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. , 2011, Human molecular genetics.

[33]  J. Cooper,et al.  Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  R. Klein,et al.  AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease , 2010, Gene Therapy.

[35]  J. Mendell,et al.  Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[36]  C. Mueller,et al.  Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[37]  R. Samulski,et al.  Cross-Dressing the Virion: the Transcapsidation of Adeno-Associated Virus Serotypes Functionally Defines Subgroups , 2004, Journal of Virology.

[38]  K. Flanigan,et al.  Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates. , 2014, Human gene therapy. Clinical development.

[39]  David J. Begley,et al.  Structure and function of the blood–brain barrier , 2010, Neurobiology of Disease.

[40]  V. Choi,et al.  AAV hybrid serotypes: improved vectors for gene delivery. , 2005, Current gene therapy.

[41]  I. Martins,et al.  Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. Mandel,et al.  Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain , 2004, Journal of Virology.

[43]  M. Wood,et al.  Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes , 2011, Nature Biotechnology.

[44]  N. Miyake,et al.  Global gene transfer into the CNS across the BBB after neonatal systemic delivery of single-stranded AAV vectors , 2011, Brain Research.

[45]  I. Martins,et al.  Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[46]  E. V. van Bommel,et al.  Mannitol-induced acute renal failure. , 1997, The Netherlands journal of medicine.

[47]  S. Cobb,et al.  Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[48]  J. Grieger,et al.  Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs , 2011, Gene Therapy.

[49]  A. Bird,et al.  Systemic Delivery of MeCP2 Rescues Behavioral and Cellular Deficits in Female Mouse Models of Rett Syndrome , 2013, The Journal of Neuroscience.

[50]  Seppo Ylä-Herttuala,et al.  Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[51]  C. Vite,et al.  Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  S. Rumpel,et al.  Analysis of Transduction Efficiency, Tropism and Axonal Transport of AAV Serotypes 1, 2, 5, 6, 8 and 9 in the Mouse Brain , 2013, PloS one.

[53]  Yoshiyuki Yamazaki,et al.  Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification. , 2012, Journal of Nippon Medical School = Nippon Ika Daigaku zasshi.

[54]  J. Wolfe,et al.  Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[55]  H. Hirai,et al.  Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice , 2013, PloS one.

[56]  R. L. Clark,et al.  Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[57]  Qin Li,et al.  Systemic scAAV9 variant mediates brain transduction in newborn rhesus macaques , 2012, Scientific Reports.

[58]  R. Samulski,et al.  Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[59]  A. Moser,et al.  Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[60]  B. Sharrack,et al.  PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[61]  J. Trempe,et al.  A helper virus-free packaging system for recombinant adeno-associated virus vectors. , 1999, Gene.

[62]  D. Schaffer,et al.  Directed evolution of adeno-associated virus yields enhanced gene delivery vectors , 2006, Nature Biotechnology.

[63]  T. Yen,et al.  Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound , 2013, PloS one.

[64]  P. Lowenstein,et al.  Crossing the Rubicon , 2009, Nature Biotechnology.

[65]  Brian M. Suzuki,et al.  Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[66]  Zeger Debyser,et al.  Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. , 2007, Human gene therapy.

[67]  A. Ballabio,et al.  Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[68]  R. Samulski,et al.  Membrane-Associated Heparan Sulfate Proteoglycan Is a Receptor for Adeno-Associated Virus Type 2 Virions , 1998, Journal of Virology.

[69]  Fabrice Marquet,et al.  Real-Time, Transcranial Monitoring of Safe Blood-Brain Barrier Opening in Non-Human Primates , 2012, 2012 IEEE International Ultrasonics Symposium.

[70]  K. Foust,et al.  Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. , 2012, Human gene therapy.

[71]  H. Fu,et al.  Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[72]  D. Hansel.  Micrometastases + Math = Model of Breast Cancer Dormancy , 2010, Science Translational Medicine.

[73]  H. Hirai,et al.  Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype. , 2016, Biomaterials.

[74]  Balaji Balakrishnan,et al.  Basic biology of adeno-associated virus (AAV) vectors used in gene therapy. , 2014, Current gene therapy.

[75]  B. Byrne,et al.  Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9 , 2012, Journal of Virology.

[76]  R. Nobre,et al.  Gene therapy for Parkinson's and Alzheimer's diseases: from the bench to clinical trials. , 2011, Current pharmaceutical design.

[77]  D. McCarty,et al.  Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis , 2001, Gene Therapy.

[78]  S. Shaffer,et al.  Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. , 2015, Human molecular genetics.

[79]  J. Muenzer,et al.  Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice , 2009, Gene Therapy.

[80]  B. Byrne,et al.  Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[81]  R. Desrosiers,et al.  Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[82]  Hynek Wichterle,et al.  Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons , 2007, Nature Neuroscience.

[83]  R. Samulski,et al.  Biology of adeno-associated viral vectors in the central nervous system , 2014, Front. Mol. Neurosci..

[84]  L. Guarente,et al.  Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway , 2016, Nature Communications.

[85]  S. Niclou,et al.  Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system , 2010, BMC Neuroscience.

[86]  C. Balagué,et al.  Adeno-associated virus Rep78 protein and terminal repeats enhance integration of DNA sequences into the cellular genome , 1997, Journal of virology.

[87]  James J. Choi,et al.  Noninvasive, transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice. , 2007, Ultrasound in medicine & biology.

[88]  Yao-Sheng Tung,et al.  A quantitative pressure and microbubble‐size dependence study of focused ultrasound‐induced blood‐brain barrier opening reversibility in vivo using MRI , 2012, Magnetic resonance in medicine.

[89]  M. Rich,et al.  Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN , 2010, Nature Biotechnology.

[90]  J. Chan,et al.  Perinatal systemic gene delivery using adeno-associated viral vectors , 2014, Front. Mol. Neurosci..

[91]  S. Salani,et al.  Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model , 2015, Science Advances.

[92]  R. Samulski,et al.  Viral vectors for gene delivery to the central nervous system , 2012, Neurobiology of Disease.

[93]  D. Shera,et al.  Long-Term Follow-Up After Gene Therapy for Canavan Disease , 2012, Science Translational Medicine.

[94]  M. Ehrlich,et al.  Lethal toxicity caused by expression of shRNA in the mouse striatum: implications for therapeutic design , 2011, Gene Therapy.

[95]  D. Yin,et al.  Efficient gene therapy-based method for the delivery of therapeutics to primate cortex , 2009, Proceedings of the National Academy of Sciences.

[96]  I. Alexander,et al.  Adeno-associated virus serotypes for gene therapeutics. , 2015, Current opinion in pharmacology.

[97]  J. Fyfe,et al.  Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[98]  S. Tsuji,et al.  Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons , 2013, EMBO molecular medicine.

[99]  H. Nakai,et al.  Characterization of genome integrity for oversized recombinant AAV vector. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[100]  K. Foust,et al.  Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes , 2009, Nature Biotechnology.

[101]  M. R. Delgado Alvira,et al.  Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues , 2004, Journal of Virology.

[102]  Theresa A. Storm,et al.  In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses , 2008, Journal of Virology.

[103]  R. Samulski,et al.  Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[104]  P. Pivirotto,et al.  Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[105]  L. Shihabuddin,et al.  Translational Fidelity of Intrathecal Delivery of Self-Complementary AAV9–Survival Motor Neuron 1 for Spinal Muscular Atrophy , 2014 .

[106]  M. Staufenbiel,et al.  Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice , 2013, Scientific Reports.

[107]  R. Samulski,et al.  A novel 165-base-pair terminal repeat sequence is the sole cis requirement for the adeno-associated virus life cycle , 1997, Journal of virology.

[108]  S. Ojeda,et al.  Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[109]  L. Alberghina,et al.  Astrogliosis as a therapeutic target for neurodegenerative diseases , 2014, Neuroscience Letters.

[110]  N. Muzyczka,et al.  Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower doses , 2008, Proceedings of the National Academy of Sciences.

[111]  N. Bessis,et al.  Immune responses to gene therapy vectors: influence on vector function and effector mechanisms , 2004, Gene therapy.

[112]  M. Weitzman,et al.  Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[113]  W. Arnold,et al.  A large animal model of spinal muscular atrophy and correction of phenotype , 2015, Annals of neurology.

[114]  B. Casto,et al.  Adenovirus-Associated Defective Virus Particles , 1965, Science.

[115]  R. Klein,et al.  Expansive gene transfer in the rat CNS rapidly produces amyotrophic lateral sclerosis relevant sequelae when TDP-43 is overexpressed. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[116]  R. Mandel,et al.  Systemic mannitol-induced hyperosmolality amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[117]  H. Hirai,et al.  Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells , 2013, The Cerebellum.

[118]  J. Wolfe,et al.  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 , 2007, The Journal of Neuroscience.

[119]  Brian L. Gilmore,et al.  Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi , 2008, Proceedings of the National Academy of Sciences.

[120]  S. Kügler,et al.  Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. , 2012, Brain : a journal of neurology.

[121]  L. Ferraiuolo,et al.  Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[122]  J. Kleinschmidt,et al.  A viral assembly factor promotes AAV2 capsid formation in the nucleolus , 2010, Proceedings of the National Academy of Sciences.

[123]  R. Samulski,et al.  Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. , 2011, Human gene therapy.

[124]  A. Grierson,et al.  Systemic Delivery of scAAV9 Expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy , 2010, Science Translational Medicine.

[125]  N. Miyake,et al.  Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector , 2014, Gene Therapy.

[126]  M. Choolani,et al.  Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems , 2012, Gene Therapy.

[127]  David Hurlbut,et al.  Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[128]  L. Belur,et al.  Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse , 2014, Front. Neuroanat..

[129]  G. Hamilton,et al.  Spinal muscular atrophy: going beyond the motor neuron. , 2013, Trends in molecular medicine.

[130]  A. Bortolozzi,et al.  Lenti‐GDNF Gene Therapy Protects Against Alzheimer's Disease‐Like Neuropathology in 3xTg‐AD Mice and MC65 Cells , 2014, CNS neuroscience & therapeutics.

[131]  E. Ayuso,et al.  Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. , 2013, The Journal of clinical investigation.

[132]  B. Byrne,et al.  Correcting Neuromuscular Deficits With Gene Therapy in Pompe Disease , 2015, Annals of neurology.

[133]  P. Grandi,et al.  Viral vectors for therapy of neurologic diseases , 2017, Neuropharmacology.