Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

McCurdy, Victoria J.; Johnson, Aime K.; Gray‐Edwards, Heather L.; Randle, Ashley N.; Brunson, Brandon L.; Morrison, Nancy E.; Salibi, Nouha; Johnson, Jacob A.; Hwang, Misako; Beyers, Ronald J.; LeRoy, Stanley G.; Maitland, Stacy; Denney, Thomas S.; Cox, Nancy R.; Baker, Henry J.; Sena‐Esteves, Miguel; Martin, Douglas R.

doi:10.1126/scitranslmed.3007733

Cited by 59 publications

(94 citation statements)

References 49 publications

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“…Clinical rating scores and neurological assessment scores of large animal research models have been reported for gene therapy in feline models of the GM1 and GM2 gangliosidoses, 13,14 canine models of Duschenne muscular dystrophy, 15 and in rabbit and canine stroke models. [16][17][18] In the current project, we hypothesize that the neurological assessment score developed for the XLMTM dog model correlates with genotype and established measures of disease severity, such as hindlimb strength.…”

Section: Introductionmentioning

confidence: 99%

Validity of a neurological scoring system for canine X-linked myotubular myopathy

Snyder¹,

Meisner²,

Mack³

et al. 2015

Human Gene Therapy Clinical Development

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A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence. A spontaneously occurring canine model has a similar clinical picture and histological abnormalities on muscle biopsy compared with patients. We developed a neuromuscular assessment score, graded on a scale from 10 (normal) to 1 (unable to maintain sternal recumbency). We hypothesize that this neurological assessment score correlates with genotype and established measures of disease severity and is reliable when performed by an independent observer. At 17 weeks of age, there was strong correlation between neurological assessment scores and established methods of severity testing. The neurological severity score correctly differentiated between XLMTM and wild-type dogs with good interobserver reliability, on the basis of strong agreement between neurological scores assigned by independent observers. Together, these data indicate that the neurological scoring system developed for this canine congenital neuromuscular disorder is reliable and valid. This scoring system may be helpful in evaluating response to therapy in preclinical testing in this disease model, such as response to gene therapy.

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Section: Introductionmentioning

confidence: 99%

Validity of a neurological scoring system for canine X-linked myotubular myopathy

Snyder¹,

Meisner²,

Mack³

et al. 2015

Human Gene Therapy Clinical Development

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“…Efficacy of gene therapy in feline GM1 gangliosidosis using intracranial injection of b-galactosidase adeno-associated virus (AAV) vectors was quantified using MRI. McCurdy et al [2014] reported normalization of brain architecture and life span, and b-galactosidase activity in the brain and spinal cord of the AAV-treated cats.…”

mentioning

confidence: 95%

MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis

Regier

Kwon

Johnston

et al. 2015

American J of Med Genetics Pt A

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Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N-acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally-invasive outcome measures for clinical trials.

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“…The comparison with AAV gene delivery to brain is difficult to establish as the resulting level of enzyme activity in different brain regions is measured in tissue blocks where the vast majority of cells are not transduced. Therefore the reported enzymatic activities of 10-to 100-fold above normal in different mouse [123,135] and cat [126,136] models of LSDs represent the activity of enzyme that is distributed throughout the brain from the target sites and now resides in non-transduced cells. Presently, there is no information on the degree of overexpression that takes place in AAV transduced cells in the target structures.…”

Section: Challengesmentioning

confidence: 99%

“…Two other clinical trials have tested AAV vectors carrying mammalian promoters such as the mouse phosphoglycerate kinase (PGK) promoter [120], or the rat neuron-specific enolase (NSE) promoter [121]. The choice of promoters is based on the availability of extensive data from pre-clinical studies in different animal models showing that AAV-mediated transgene expression under these promoters is stable and long lasting in the mammalian brain [122][123][124][125][126][127]. The stability of AAV gene expression in the human brain has been evaluated in clinical trials using an AAV2 vector encoding aromatic amino acid decarboxylase (AADC) injected into the putamen of Parkinson's disease patients [116], or children afflicted with AADC deficiency [115].…”

Section: Challengesmentioning

confidence: 99%

“…A number of methods are being explored to achieve more global delivery in the brain, including: convection enhanced delivery [210]; introduction into a fluid space, e.g., vasculature, brain ventricles [197] or intrathecal space in the spinal cord [211], such that cells lining the space produce the deficient protein; injection into regions of the brain that serve as a nexus of interconnections with retrograde transport of vectors, such as the thalamus, e.g., for AAV [126]; and/or by taking advantage of the "bystander effect" whereby proteins released from the producer cells can be taken up by the deficient cells [126,197].…”

Section: Compartmental Vs Global Deliverymentioning

confidence: 99%

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Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

Cited by 59 publications

References 49 publications

Validity of a neurological scoring system for canine X-linked myotubular myopathy

Validity of a neurological scoring system for canine X-linked myotubular myopathy

MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis

Gene Therapy for the Nervous System: Challenges and New Strategies

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