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Intrathecal administration of AAV9 permits dissemination of transgenes throughout the nervous system and is currently in clinical trials for the treatment of neuronal ceroid lipofuscinosis 3 CLN3; ClinicalTrials.
However, intrathecal administration has many advantages, including higher transduction efficiency of the CNS 20 ; sustained expression with the absence of toxicity 21 seen with systemic delivery 22 ; evasion of anti-AAV neutralizing antibodies 23 , which have been shown to be detrimental to systemic delivery 24 ; and requirement of substantially less vector product, increasing the feasibility of translation to human patients.
Intrathecal AAV9-mediated gene therapy for Krabbe disease was first evaluated in the twitcher mouse 25 , This treatment improved the pathology and reduced psychosine levels but did not restore them to baseline levels Notably, at postnatal day 10—11, twitcher mice are postsymptomatic, with reduced body weight and disease pathology present.
Presymptomatic intrathecal injections were not performed, presumably because of the small size of the newborn mouse and the compressed timeline of disease progression.
Vector was administered at the cisterna magna, since we and others have shown that intracisternal AAV9 administration is safe in cats, dogs, and nonhuman primates and results in up to fold more efficient gene transfer to the brain than does administration via lumbar puncture 27 or intravenously Intracisternal AAV9 is currently being administered to patients with mucopolysaccharidosis I NCT and GM1 gangliosidosis NCT in clinical trials, making this a clinically relevant route of administration.
These dogs continue to be monitored by neurological examination, MRI, nerve conduction velocity testing, and brainstem auditory evoked response.
Serum and CSF samples are routinely collected for additional long-term analyses. The results in the dog far exceed expectations based on the findings in the twitcher mouse.
Additionally, the twitcher mouse results from a nonsense mutation c. Twitcher mice dosed intrathecally with AAV9-mGALC did not receive immunosuppression 15 and thus may have developed an immune response that diminished transgenic protein expression.
In fact, CNS-directed AAV-mediated gene therapy has previously been shown to elicit an immune reaction even in newborn twitcher mice In contrast, GLD in the dog results from a missense mutation c.
In addition to this immunological advantage, GLD dogs received high-dose immunosuppression before gene transfer and maintenance immunosuppression for 4 months, preventing immune-driven decreases in transgenic protein expression.
The delayed progression of motor deficits seen in these dogs correlates with normalization of cerebellar white matter signal intensity and cerebellar area on MRI.
While cerebellar disease was ameliorated, pathological signs emerging in 2Wk-Low—treated dogs included behavioral abnormalities and visual deficits.
Blindness is likely central in origin as no retinal abnormalities were observed and demyelination and perivascular cuffing were observed in the occipital lobes.
Fascinatingly, these clinical findings are similar to those in late-infantile-onset and juvenile-onset patients, who all fall below the 5th percentile in cognitive development by 40 months of age, with vision deterioration observed in the majority 3.
Additionally, the canine model of GLD allowed for comparison of pre- and postsymptomatic gene delivery. Our studies found that postsymptomatic therapy was less effective than presymptomatic therapy at the respective doses evaluated.
This outcome stands in stark contrast to HSCT, which is only effective presymptomatically 6. We speculate that postsymptomatically treated dogs did not fare as well as those treated presymptomatically because of reduced vg dose relative to their larger brain and body size at the time of treatment.
Two-week-old normal dogs from this specific breeding line have an average brain weight of Based on this, the dogs in the 2Wk-High cohort received an estimated 3.
Notably, the single remaining dog in the 6Wk-High cohort, currently While systemic delivery of AAV is conventionally normalized to body weight, our data suggest that intrathecal delivery of AAV would also benefit from normalization to body weight, estimated brain weight, or CSF volume.
As such, we predict that normalization of dosing is likely to further improve prognosis for dogs treated postsymptomatically. Krabbe disease in patients results from more than pathogenic variants.
In patients of northern European decent, a kb deletion and 2 missense mutations, c. TM and c. While the naturally occurring canine model has genetic limitations, the missense mutation may be representative of a large population of Krabbe disease patients and how they would respond to gene therapy.
Since we were able to establish a robust, clinically relevant biomarker in the canine model, this could potentially be useful to normalize therapeutic responses among different mutations.
In Krabbe disease patients, psychosine is a diagnostic marker of phenotype severity and treatment effect 30 , Similarly, we have shown that CSF psychosine increased early and steadily in untreated GLD and strongly correlated with disease progression In the 2Wk-High cohort, CSF psychosine remained undetectable up to 24 weeks, and from 24 to 52 weeks psychosine was detected in the CSF of only 1 dog, which currently remains asymptomatic.
If psychosine is indeed a robust biomarker of therapeutic outcome, we predict that this one dog will eventually fare less well than other dogs in the cohort.
CSF protein concentration has recently been shown to predict age of disease onset and survival in a study of Krabbe disease patients 4.
Comparably, we show that CSF protein increases early and steadily, with levels rising above normal in untreated GLD dogs by 8 weeks of age.
Notably, CSF protein concentration in the 2Wk-High cohort remains within normal levels beyond 52 weeks of age, consistent with their increased longevity and reduced pathology.
Postmortem evaluation of the 2Wk-High cohort at 16 weeks of age demonstrated global transduction of the CNS with a significant increase in GALC enzyme activity and significant reduction in psychosine concentration in the most rostral brain region sampled, the frontal cortex.
GALC enzyme activity levels approximately 4 times normal were seen in the cerebellar white matter, the tissue sampled closest to the injection site.
Interestingly, psychosine concentration was below normal levels in this brain region. Despite attainment of supraphysiological levels of a normally low-expressing enzyme, no evidence of toxicity was noted in any dog, and no lesions were noted on MRI or on histological evaluation near the injection site.
MRI lesions have previously been demonstrated in nonhuman primates, in which toxicity due to overexpression of a different secreted hydrolytic lysosomal enzyme occurred Variability in tissue psychosine concentrations and GALC activity was minimal within the 2Wk-High cohort, all sacrificed at 16 weeks of age, signifying reproducibility of this treatment approach.
In contrast, variability was seen within the IS-only and 2Wk-Low cohorts, which were followed until humane endpoint. We recently reported that CSF psychosine concentrations vary and closely correlate with disease progression in GLD dogs 16 , and this is likely true for tissues.
Interestingly, the youngest dog to develop pelvic limb paralysis in the IS-only cohort had the highest psychosine levels in the sciatic nerve Dog 1, Supplemental Table 1.
Similarly, in the 2Wk-Low cohort, the single dog that reached humane endpoint solely due to pelvic limb paralysis and not combinatorial factors of blindness and behavior concerns had the highest psychosine concentration in the sciatic nerve Dog 16, Supplemental Table 1.
It is hypothesized that assessment of psychosine concentrations following biopsy of peripheral nerves in patients may yield important information regarding clinical outcome.
Psychosine concentrations were highest in all cohorts in the internal capsule. The internal capsule was the single nervous system tissue in which presymptomatic high-dose AAV did not normalize psychosine and GALC and did not achieve a significant increase in vg copies.
It is probable that psychosine had already accumulated to irreversible levels by the time of treatment at 2 weeks of age or, alternatively, cell death and globoid cell formation in this area did not allow for sufficient transduction of therapeutic GALC.
It has recently been shown in the twitcher mouse that inhibitory effects of psychosine are visible as early as embryonic day 12 Taken together, these findings reiterate the importance of early intervention.
Biochemical findings were corroborated by MRI and histology. In the 2Wk-High cohort, T2-weighted hyperintensity was most apparent on MRI at the centrum semiovale, a region for pathology initiation in Krabbe disease 34 , Notably, the lesion was stable from 16 to 52 weeks, suggesting that pathology was likely present at the time of treatment and did not progress thereafter.
Histology confirmed this to be a region of demyelination, necrosis, and globoid cell accumulation.
The same distribution was seen in the 2Wk-Low cohort, but in greater intensity likely due to the prolonged age. The 2Wk-High cohort demonstrated cortical neurons and Purkinje cells strongly expressing GALC to a greater degree than normal age-matched controls, suggesting either the transduction of these cells or the accumulation of GALC due to mannosephosphate receptor—mediated endocytosis.
The ability of the enzyme to actively cleave a substrate as measured by enzyme assay is more revealing as to the effect of AAV-delivered GALC.
Intrathecally delivered AAV vectors are redistributed from the subarachnoid space to systemic circulation likely via the arachnoid villi However, recent identification of the glymphatic, or glia-associated lymphatic, system has provided more insight into additional mechanisms that may control AAV clearance.
Dysregulation of membrane channels in aged and diseased mouse brains correlated with significantly increased retention of AAV vectors in the brain and reduced systemic leakage This has yet to be investigated in Krabbe disease.
Although effective therapies for CNS disease are being developed, the current inability to treat peripheral neuropathies continues to impact the prognosis for patients with many lysosomal storage diseases.
While cognitive function is improved in infants with Krabbe disease who receive HSCT, motor deficits and peripheral nerve dysfunction often persist 6 , 37 , Here, in the canine GLD model, early delivery of high-dose, but not low-dose, AAV9-cGALC resulted in a significant increase in GALC enzyme activity and significant reduction of psychosine to below normal levels in the sciatic nerve after intracisternal delivery.
The increase in sciatic nerve GALC activity could be due either to transduction of the lower motor neuron or dorsal root ganglia, resulting in increased axonal GALC, or to transduction of Schwann cells.
The delivery of lysosomal enzymes to Schwann cells and axons of peripheral nerves has been previously described in dogs with mucopolysaccharidosis VII that received canine GUSB via intracisternally delivered AAV 39 and likely results from AAV passage down the nerves through endoneurial fluid 40 — 42 or axonal transport 43 , Importantly, in this study, nerve conduction velocity testing and PNS ultrastructure analysis show improved PNS myelination in treated dogs and corroborate the biochemical findings.
Together, these findings provide what is to our knowledge the first demonstration of clinical, biochemical, and histological correction of PNS abnormalities in a large-animal model following intracisternal delivery of AAV9.
This finding holds implications for treatment of other peripheral nerve disorders using this safe, effective, and proven route of administration.
We previously evaluated combination intravenous and intracerebroventricular administration of AAVrh10 in canine GLD The studies cannot be directly compared because of different AAV serotypes, routes of administration, doses, and immunosuppression protocols.
Nonetheless, intracisternal AAV9 evaluated herein resulted in what we believe to be the first extension of lifespan beyond 1 year of age in the GLD dog and more global correction of nervous system disease.
Additionally, intracisternal delivery allowed for earlier intervention and required significantly less vector, permitting higher dosing and a more robust study design.
Intracisternal AAV9 has shown unprecedented results in this large-animal model and is the most translatable approach evaluated to date.
Reducing the dose 5-fold resulted in significant extension of lifespan; however, an attenuated form of Krabbe disease developed, including behavioral abnormalities and blindness.
These results reiterate findings from other AAV9 clinical trials that high-dose and early intervention are necessary for AAV9 to provide the greatest benefit.
In light of safety data of intrathecal delivery of AAV9 emerging from clinical trials for other diseases, we believe that this positive finding in a large-animal model of Krabbe disease warrants timely translation to the clinic.
Animals, immunosuppression, and AAV vector injections. Whole blood from dogs was tested for the GALC mutation as previously described 12 , Then 1.
Dogs received oral prednisone at a dose of 0. GLD dogs were euthanized using an overdose of intravenous barbiturate at a predetermined or standard humane endpoint.
After sacrifice, animals were perfused through the left ventricle with 0. Vector production. Nerve conduction velocity, brainstem auditory evoked response, and MRI.
Dogs were anesthetized with propofol, endotracheally intubated, and maintained on isoflurane anesthesia. Nerve conduction velocity was tested using an electrodiagnostics machine Nicolet Viking Quest.
Brainstem auditory evoked response data were recorded using a Nicolet Viking Quest machine Nicolet Biomedical.
Imaging was performed on anesthetized dogs on a 1. Nerve conduction velocity testing, brainstem auditory evoked response recording, and MRI were performed as previously described 12 , 13 , Myelin staining and periodic acid—Schiff staining were performed as previously described 12 , For immunofluorescence, deparaffinized and rehydrated slides were heated to a boil followed by a minute incubation in antigen retrieval solution HK, Biogenex.
Show all 19 episodes. Lexi Branson. Show all 9 episodes. The Girl voice. Stephanie's Friend. Underground Video Chloe. Vanessa Shaw. Show all 16 episodes.
Nicole Carr. Payton voice. Naomi Nahar. Paige Thomas. Show all 7 episodes. Sydney Blair. Pam Carpenter. Taya uncredited. Lindsay Forester.
Andrea Kent. Paige Lange. Right Teen. Self - Guest. Self - Panelist. Filming took place in late in Vancouver , British Columbia.
Despite performances of the cast being well received, critical reception was mixed to negative. In early December , Kebbel landed a recurring role in season four of portraying Vanessa.
From Wikipedia, the free encyclopedia. American actress and model. Winter Park, Florida , U. WALB News. Archived from the original on October 19, Retrieved July 29, Retrieved 25 August I am so grateful to do this life with you… " ".
Retrieved Retrieved November 8, Categories : births 21st-century American actresses Actresses from Florida American beauty pageant contestants American beauty pageant winners American film actresses American game show hosts American people of German descent American television actresses Female models from Florida Living people People from Winter Park, Florida Actresses of German descent.
Namespaces Article Talk. Views Read Edit View history. Help Learn to edit Community portal Recent changes Upload file.Bei Ihrer Anfrage ist ein Problem aufgetreten. Schafft sie es Boris Becker Der Spieler, verwandelt sie sich Mediathekview 13 in eine Meerjungfrau und ihre Seele gehört Ursula. Amazon Business Kauf auf Rechnung. Für die musikalische Leitung war Andreas Hommelsheim zuständig. Jetzt entdecken. Interestingly, in the cerebellar white matter and sciatic nerve, where Das Große Backen Ganze Folgen enzyme activity exceeded normal Figure 8Bpsychosine levels were 1. SJG has received research funding from Neurogene and Texas Chainsaw Massacre Stream Deutsch Movie2k and has received income from Neurogene consulting and DonT Breathe Stream Hd and Vertex Pharmaceuticals consulting. In contrast to all other cohorts, in week-old dogs in the 2Wk-High cohort, strong GALC expression in the majority of neurons of cortical layer V was detected Figure 5G. While Die Nervöse Republik disease was ameliorated, pathological signs emerging in 2Wk-Low—treated dogs included behavioral abnormalities and visual deficits. Um dieses Ziel zu erreichen, holte er Alan Menken an Donald Bellisario, mit dem er zusammen sieben verschiedene Songs komponierte. Download as PDF Printable version. Schlussendlich umfasste das Drehbuch rund 20 Seiten bis Clements vollständig zufrieden war. Sie findet sich auch in den folgenden Disneyfilmen immer wieder. In fact, presymptomatic delivery of high-dose AAV increased lifespan to Ndr Sh Magazin than 7 times Dinosaurus of untreated GLD dogs, with all treated dogs remaining neurologically normal beyond 1.
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Arielle Krabbe Contribute to This Page VideoArielle die Meerjungfrau. Sebastian die Krabbe wird mit der wäsche mit gewaschen ;-)