Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

Meyer, Kathrin; Ferraiuolo, Laura; Schmelzer, Leah; Braun, Lyndsey; McGovern, Vicki L.; Likhite, Shibi; Michels, Olivia; Govoni, Alessandra; Fitzgerald, Julie; Morales, Pablo; Foust, Kevin D.; Mendell, Jerry R.; Burghes, Arthur H.M.; Kaspar, Brian K.

doi:10.1038/mt.2014.210

Cited by 221 publications

(241 citation statements)

References 52 publications

(66 reference statements)

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“…No significant changes in weight gain or serum chemistry profiles were observed throughout the study, nor was there any evidence of systemic inflammation as measured by the presence of serum cytokines/chemokines (data not shown). These findings demonstrate that the scAAV9 constructs did not induce toxicity or systemic inflammation, which is in agreement with prior reports using scAAV9 in both mice and nonhuman primates (Foust et al, 2013;Garg et al, 2013;Meyer et al, 2015).…”

Section: Systemic Administration Of Scaav9 Successfully Crosses the Bsupporting

confidence: 82%

“…Gene delivery via self-complementary adeno-associated virus 9 (scAAV9) has shown benefits in multiple neurodegenerative diseases, including spinal muscular atrophy and Rett syndrome (Gadalla et al, 2013;Garg et al, 2013;Meyer et al, 2015). AAV9 is an effective vector for CNS delivery after systemic (intravenous) injection because it crosses the blood-brain barrier and transduces both neuronal and non-neuronal cells (Foust et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Bosch¹,

Aldrich

Fallet

et al. 2016

J. Neurosci.

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal-recessive mutations in CLN3 for which no treatment exists. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline and premature death (late teens to 20s). We explored a gene delivery approach for JNCL by generating two self-complementary adeno-associated virus 9 (scAAV9) constructs to address CLN3 dosage effects using the methyl-CpG-binding protein 2 (MeCP2) and ␤-actin promoters to drive low versus high transgene expression, respectively. This approach was based on the expectation that low CLN3 levels are required for cellular homeostasis due to minimal CLN3 expression postnatally, although this had not yet been demonstrated in vivo. One-month-old Cln3 ⌬ex7/8 mice received one systemic (intravenous) injection of scAAV9/MeCP2-hCLN3 or scAAV9/␤-actin-hCLN3, with green fluorescent protein (GFP)-expressing viruses as controls. A promoter-dosage effect was observed in all brain regions examined, in which hCLN3 levels were elevated 3-to 8-fold in Cln3 ⌬ex7/8 mice receiving scAAV9/␤-actin-hCLN3 versus scAAV9/MeCP2-hCLN3. However, a disconnect occurred between CLN3 levels and disease improvement, because only the scAAV9 construct driving low CLN3 expression (scAAV9/MeCP2-hCLN3) corrected motor deficits and attenuated microglial and astrocyte activation and lysosomal pathology. This may have resulted from preferential promoter usage because transgene expression after intravenous scAAV9/MeCP2-GFP injection was primarily detected in NeuN ϩ neurons, whereas scAAV9/␤-actin-GFP drove transgene expression in GFAP ϩ astrocytes. This is the first demonstration of a systemic delivery route to restore CLN3 in vivo using scAAV9 and highlights the importance of promoter selection for disease modification in juvenile animals.

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Section: Systemic Administration Of Scaav9 Successfully Crosses the Bsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Bosch¹,

Aldrich

Fallet

et al. 2016

J. Neurosci.

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“…Gene replacement by intravascular AAV9 administration has proved effective in preclinical studies in both mice and non-human primates (Foust et al, 2010; Bevan et al, 2010; Passini et al, 2014; Meyer et al, 2015; Duque et al, 2015). Based on these studies, a Phase I clinical trial (NCT02122952) with intravenous administration of AAV9-SMN1 has been initiated in babies 2–9 months of age (https://clinicaltrials.gov/ct2/show/NCT02122952).…”

Section: Different Modalities For Different Diseasesmentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

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“…AAV9 can cross the blood-brain barrier and transduce nondividing cells, such as motor neurons, without integration of the host cell's genome (48). To increase transduction efficacy and expression of SMN, double stranded self-complementary AAV9 (scAAV9) vectors have been used and several parameters (life span, motor functions, safety, and delivery route) have been tested using mice, pig, and nonhuman primates as model organisms (50,(72)(73)(74)(75). Owing to encouraging preclinical results, FDA has been approved for the first clinical trials in humans with scAAV9-SMN1, under the name AVXS-101.…”

Section: Gene Therapymentioning

confidence: 99%

“…Therefore, increasing SMN protein level is the most straightforward approach for SMA therapy, and has been studied for years with different strategies such as correction of SMN2 splicing, modulation of SMN gene expression, prevention of protein degradation, and replacement of SMN1 (reviewed in 3,33-37). Significant efforts have been made to develop or identify effective small molecules (38)(39)(40)(41)(42)(43)(44), antisense oligonucleotides (45)(46)(47), and viral vectors (48)(49)(50) in order to increase SMN in preclinical research. The efficacy of some of the above has been tested in clinical trials.…”

Section: Introductionmentioning

confidence: 99%