AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease

In the paper

“Although the gene packaging size is limited (maximum 5.0 kb), typically the relevant gene coding sequences can be easily packaged for CNS delivery.”

What the sources say

• Partly supported

  Sections 1 and 2 confirm that AAV packaging capacity is limited, but they give a maximum of about 4.5 kb, not 5.0 kb. Section 2 further specifies 4.5 kb for single-stranded vectors and 2.4 kb for self-complementary vectors. (LLM, conf=0.88)

  cites [52] sourceExperimental — accuracy not yet measured
• Disputed

  The Discussion states that AAV packaged vector genomes as large as 6 kb with similar efficiency, contrary to the claimed 5.0-kb maximum. The paper distinguishes packaging capacity from the reduced infectivity of some larger-genome vectors. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [67] sourceExperimental — accuracy not yet measured

In the paper

“AAV5 transduces only granular cells”

What the sources say

• Disputed

  The Results section, “Analysis of cell-type tropism for various serotypes” (page unavailable), reports GFP expression in every cell type analyzed with each injected serotype, including rAAV5—not only granular cells. The Discussion also reports rAAV5 transduction of excitatory neurons in the lateral entorhinal cortex. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  cites [69] sourceExperimental — accuracy not yet measured

In the paper

“Use of intrathecal delivery for gene therapy vectors has been limited to studies involving spinal cord and peripheral nerve disease.”

What the sources say

• Disputed

  In “AAV serotypes and off-target biodistribution” (page unavailable), the paper says intrathecal AAV9 was in preclinical development for mucopolysaccharidosis IIIA as well as giant axonal neuropathy, and describes its transduction of both the central and peripheral nervous systems. The References section identifies a study of intracerebrospinal-fluid gene therapy for whole-body correction of mucopolysaccharidosis IIIA. Thus, the paper does not limit studies of this delivery route to spinal cord and peripheral nerve disease. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  cites [90] Pleticha J, 2014, Mol Pain sourceExperimental — accuracy not yet measured
• Partly supported

  The passage discussing PNS gene therapy (indexed under References; page unavailable) identifies intrathecal delivery of rAAV vectors among techniques studied for peripheral sensory conditions, including neuropathic pain. It does not say that intrathecal vector delivery has been limited to spinal cord and peripheral nerve disease studies; that restriction is unsupported. (LLM, conf=0.82)

  cites [91] sourceExperimental — accuracy not yet measured
• Disputed

  The Results section, “AAV9 injection into the CSF produces transgene expression in the brain” (page unavailable), reports examining brain expression after intrathecal or cisternal vector injection in piglets. The paper therefore does not confine its investigation of intrathecal gene delivery to spinal cord and peripheral nerve disease, as the claim says. (LLM, conf=0.81)

  Checked by a reasoning model — may be wrong.

  cites [92] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [93] source

In the paper

“as well as an earlier age of onset for developing the disease (approximately 5 years for each APOE4 allele compared to APOE3 homozygotes).6,9,10”

What the sources say

• Partly supported

  The Results (page not provided) compare APOE4 genotypes with APOE3 homozygotes across age-of-onset groups, and the paper says APOE4 is a risk factor for early-onset Alzheimer’s disease. It does not report an onset approximately five years earlier for each APOE4 allele. (LLM, conf=0.83)

  cites [6] Genin E, 2011, Mol Psychiatry sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [9] source
• Partly supported

  The Discussion reports earlier onset of late-onset Alzheimer’s disease with each APOE ε4 allele, but estimates about three years per allele, not five. The Results also report no significant effect on age at onset in early-onset Alzheimer’s disease. (LLM, conf=0.90)

  cites [10] Sando SB, 2008, BMC Neurol sourceExperimental — accuracy not yet measured

In the paper

“There are three common APOE alleles (E2, E3, and E4), each encoding APOE isoforms expressed primarily in the liver and brain.7,8”

What the sources say

• Supported

  The ‘STRUCTURE OF THE ApoE ISOFORMS’ section identifies apoE2, apoE3, and apoE4 as three distinct isoforms, and ‘ApoE AND ALZHEIMER DISEASE’ refers to the apoE4 allele. ‘A New Role for ApoE: Neuropathology’ says apoE is produced abundantly in the brain, second only to the liver, supporting the stated primary sites of expression. The paper does not explicitly call all three alleles common, but its account supports the substance of the paraphrase. (LLM, conf=0.86)

  cites [7] source
• ?Not checked — no full text of the sourcecites [8] source

In the paper

“Currently approved drugs do little to limit disease progression, and no preventive therapies are available.3,4”

What the sources say

• Supported

  The Introduction lists five approved Alzheimer’s drugs and says drugs to prevent or slow the disease are urgently needed. The Discussion describes the approved memantine as a symptomatic treatment and reports that none of the agents assessed for disease-modifying potential showed a benefit on primary outcomes. Together, these passages support the claim as a description of the situation at the time of publication. (LLM, conf=0.88)

  cites [3] source
• Supported

  The Conclusions (page not provided) say current AD drugs are essentially symptomatic and do not arrest dementia progression. The Abstract and the active-immunotherapy section describe approaches to prevention as investigational, while the Conclusions identify only symptomatic drugs as current treatment; together, these support the statement that no preventive therapy was available. (LLM, conf=0.87)

  cites [4] source

In the paper

“The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges (total 65 blood samples from 29 individual male NHPs) and establish the upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.31,35”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [31] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [35] Sondhi D, 2016, Mol Ther source

In the paper

“Due to the small sample size (n = 3/group) and daily variations in cell numbers and serum chemistries, statistical comparisons were considered to be significant if p < 0.01.31,37,38”

What the sources say

• Partly supported

  The Results (page unavailable) report statistical comparisons of serum chemistry and blood-count measurements. They describe n=2 monkeys per route, except n=1 for the intraarterial route, rather than n=3 per group. The passages do not state a p<0.01 significance threshold or attribute one to daily variation in cell numbers and serum chemistries. (LLM, conf=0.86)

  cites [31] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [37] source
• ?Not checked — no full text of the sourcecites [38] source

In the paper

“Studies with a lentiviral vector expressing APOE2 delivered directly to the hippocampus of a transgenic AD mouse established a robust protective effect of the APOE2 allele on AD risk, with an observed rapid, significant reduction in brain amyloid burden and neuritic plaques.23”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [23] sourceExperimental — accuracy not yet measured

In the paper

“Targeting the large cerebral ventricles (intraventricular route) in the frontal lobe of the brain is an easy surgical task, and is commonly used to deliver drugs to the CNS.”

What the sources say

• Partly supported

  The Experimental Procedures (page not provided) describe stereotaxic injections into rats’ lateral ventricles, and the Discussion describes prior intraventricular delivery of IGF-1. These passages support use of the route to deliver a therapeutic agent, but do not establish that targeting ventricles in the frontal lobe is an easy surgical task or that the route is commonly used for drugs generally. (LLM, conf=0.84)

  cites [85] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [86] Pardridge WM, 2016, Expert Opin Drug Deliv source
• Partly supported

  The Abstract and Discussion say that delivery into the brain ventricles is commonly used to administer peptides and pharmacological agents to the CNS. They do not describe the ventricles as being in the frontal lobe or targeting them as an easy surgical task. The Abstract instead notes technical drawbacks and says that installing and manipulating an ICV pump requires complex surgery. (LLM, conf=0.88)

  cites [87] sourceExperimental — accuracy not yet measured
• Partly supported

  Materials and Methods (rhTPP1 Formulation and Administration; page unavailable) describes a catheter placed in a lateral ventricle and used to infuse treatment into the CNS. It does not say the ventricle was targeted in the frontal lobe, that placement was an easy surgical task, or that this route is commonly used for CNS drug delivery. (LLM, conf=0.85)

  cites [88] sourceExperimental — accuracy not yet measured

In the paper

“This has the advantage of increased vector volume that can be delivered to the target site, which enhances cell transduction in the targeted CNS substructure”

What the sources say

• Partly supported

  The Introduction (page unavailable) says convection-enhanced delivery distributes vector at higher concentrations over a larger area than diffusion alone. The Results, ‘Distribution of hrGFP within the brain’ (page unavailable), report transduction volumes larger than the infused volumes. Neither passage establishes that CED increases the amount of vector that can be delivered to a target site; the claim appears to conflate delivered volume with distribution or transduction volume. (LLM, conf=0.84)

  cites [78] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes CED as a means of distributing viral vectors to brain targets, and Methods §2.1 reports vector co-infusions of 30–300 μL. The paper does not show that CED increases the volume of vector that can be delivered relative to another method or that a larger volume enhances cell transduction in the targeted CNS structure. (LLM, conf=0.84)

  cites [79] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [80] source

In the paper

“Of these AAV serotypes, the most commonly used for clinical trials to date are AAV5, AAV9, and AAVrh.10.”

What the sources say

• Partly supported

  Section 4.1 identifies AAV9 and AAVrh10 as capsids used in more recent clinical trials. It does not identify AAV5 as commonly used in trials or establish that these three are the most commonly used serotypes; Section 3.1 discusses AAV5's cell-transduction pattern instead. The paper also says AAV2 was used in all first-generation trials. (LLM, conf=0.86)

  cites [52] sourceExperimental — accuracy not yet measured
• Partly supported

  The Lysosomal storage disorders section describes clinical trials using AAV5, AAV9, and AAVrh.10. But neither that section nor the Introduction establishes that these are the most commonly used serotypes in clinical trials; the Introduction also describes AAV2 trials. The source supports their clinical use, not the claimed ranking. (LLM, conf=0.87)

  cites [56] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [58] source
• Partly supported

  The Overview of Adeno-associated Virus-mediated CNS Gene Therapy discusses AAV5, AAV9, and AAVrh.10, and Lessons Learned and Path Forward describes an AAVrh.10 clinical trial. But the paper does not say these are the most commonly used serotypes in clinical trials; its discussion of AAV5 concerns earlier studies, and it mentions AAV9 as a discovered serotype, not as a clinical-trial vector. (LLM, conf=0.85)

  cites [71] sourceExperimental — accuracy not yet measured

In the paper

“AAV vector administration to the CNS has an excellent safety and efficacy profile.”

What the sources say

• Partly supported

  Section 2 describes AAV vectors as close to ideal for CNS gene therapy, citing low toxicity and mild immunogenicity. But section 4.1 reports that clinical trials were less effective, with no significant improvement in one trial and only minor improvement in another. The paper supports a favorable safety profile, but not a generally excellent clinical efficacy profile. (LLM, conf=0.87)

  cites [52] sourceExperimental — accuracy not yet measured
• Partly supported

  Section 5.1 describes AAV vectors as suitable for brain gene delivery because of their low immunogenicity and reports effective transduction. Section 7 reports that an AAV2 trial was safe and well tolerated, but says its efficacy was still being evaluated; the paper also reports AAV9 immune activation and possible neurotoxicity in Section 5.1. These qualifications do not support an unqualified claim of an excellent safety and efficacy profile for CNS AAV administration. (LLM, conf=0.88)

  cites [53] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [55] source
• Supported

  The Introduction reports remarkable evidence of efficacy and safety for rAAV vectors in numerous animal models and says their safety helps make them commonly used for CNS gene therapy. The Perspective describes encouraging early clinical results, while noting that further improvements in safety and efficacy are needed. (LLM, conf=0.88)

  cites [56] source
• ?Not checked — no full text of the sourcecites [57] source
• ?Not checked — no full text of the sourcecites [58] source
• Partly supported

  The Abstract (page not supplied) reports no long-term adverse events related to AAV2 and preliminary benefits in 13 patients with Canavan disease. The Discussion says the positive clinical and imaging findings need validation in a larger trial. These findings do not establish an excellent safety and efficacy profile for AAV administration to the CNS generally. (LLM, conf=0.88)

  cites [59] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [60] source
• ?Not checked — no full text of the sourcecites [61] source
• ?Not checked — no full text of the sourcecites [62] source

In the paper

“AAV vector-mediated gene therapy has become a preferred method for delivering therapeutic genes to the CNS.”

What the sources say

• Supported

  Section 2 describes AAV vectors as among the most important for neurological therapy, the most frequently used viral vectors in CNS clinical trials, and close to an ideal CNS gene-therapy vector. Section 4.5 also calls them a leading vehicle for in vivo gene transfer, including to the brain. These passages support the claim's characterization of AAV as a preferred delivery method. (LLM, conf=0.94)

  cites [52] source
• ?Not checked — no full text of the sourcecites [66] Golebiowski D, 2015 source

In the paper

“the amyloid deposition spreads, and the disease pathogenesis progressively involves a broad region of the brain”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports fibrillar amyloid-β burden across several brain regions associated with AD, supporting the claim that deposition involves a broad region of the brain. But the paper does not establish that deposition spreads over time or that disease pathogenesis progressively involves more regions; the Discussion notes the absence of longitudinal amyloid data. (LLM, conf=0.85)

  cites [20] Reiman EM, 2009, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) describes amyloid accumulation in several cortical regions, supporting the claim that pathology involves multiple brain regions. It does not establish that deposition spreads progressively; the Discussion’s limitations say the cross-sectional study cannot determine whether biomarker changes are ongoing. (LLM, conf=0.84)

  cites [43] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes AD as a progressive neurodegenerative disorder, and the Results report abnormalities in the hippocampus and amygdala. But the paper’s passages do not say that amyloid deposition spreads or that pathology progressively extends across a broad region of the brain; the findings concern specific structures rather than brain-wide progression. (LLM, conf=0.82)

  cites [44] Tang X, 2016, Magn Reson Imaging sourceExperimental — accuracy not yet measured

In the paper

“an additional non-surgical route—intranasal—has been tested delivering AAV9 via the nasal cavity in mice for mucopolysaccharidosis I, resulting in widespread detection of the transgene activity across the CNS”

What the sources say

• Supported

  The Materials and Methods describe delivery of AAV9-IDUA into the nasal cavity of MPS I mice. The Results report IDUA enzyme activity in the olfactory bulb and other brain regions, and the Discussion also reports activity in the spinal cord. This supports widespread detection of transgene-derived activity across the CNS, though it does not establish widespread cellular transduction. (LLM, conf=0.90)

  cites [96] source

In the paper

“the hippocampal region is important to short-term memory loss in AD and is the earliest region involved in the progression of the disease”

What the sources say

• Partly supported

  The Discussion (page not supplied) links vulnerability of the hippocampal CA1 region to memory impairment in AD. But the paper identifies marked entorhinal-cortex changes in very mild AD; it does not establish that the hippocampal region is the earliest region involved or specifically attribute short-term memory loss to it. (LLM, conf=0.84)

  cites [39] Gomez-Isla T, 1996, J Neurosci sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (LEC versus MEC dysfunction; page unavailable) link impaired delayed retention in early Alzheimer’s disease to the lateral entorhinal cortex, and the Discussion links that task to hippocampal-dependent memory. But the paper identifies the lateral entorhinal cortex—not the hippocampus itself—as the primary early site of dysfunction, so it does not support calling the hippocampus the earliest region involved. (LLM, conf=0.87)

  cites [40] sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion and Image analysis sections report early hippocampal atrophy in people with MCI who later developed AD, but identify several other medial temporal regions with early loss; they do not establish the hippocampus as the single earliest region. The passages do not link hippocampal atrophy specifically to short-term memory loss. (LLM, conf=0.87)

  cites [41] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Results link hippocampal CA1 circuits to spatial-memory impairment in AD mice, supporting a role for the hippocampal region in memory loss. They do not identify the impairment as short-term memory loss. The Introduction instead identifies entorhinal-cortex neurons as particularly vulnerable early in AD; it does not say the hippocampus is the earliest region involved. (LLM, conf=0.86)

  cites [42] Yang X, 2018, Mol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“the connection to the entorhinal cortex, the olfactory bulb, is directly affected by changes in the perforant pathway, and one of the earliest pathological changes in AD”

What the sources say

• Partly supported

  The Discussion (page unavailable) says that brain regions involved in olfaction are vulnerable to AD pathology and reports reduced entorhinal cortical thickness. It does not say that the olfactory bulb is directly affected by perforant-pathway changes or that this is among the earliest pathological changes in AD. (LLM, conf=0.82)

  cites [43] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [49] source

In the paper

“The same pattern was observed for the intraventricular route (treated, DNA 90.0% cubes, control 3.9% cubes; mRNA treated 86.0% cubes, control 2.9% cubes; and protein 51.5% cubes, control 3.0% cubes; Table 3).”

In the paper

“Histopathological examination of the brain left frontal lobes from the dual-route NHPs (NHP-10–NHP-12) revealed focal lesions in the gray matter with minor histiocytic infiltrate and hemosiderosis in the gray matter (Supplementary Fig. S7A–F) and multifocal gliosis with histiocytic infiltrate, hemosiderosis, spongiosis, and vascular hyperplasia in the underlying white matter (Supplementary Fig. S7”

In the paper

“There was heavy staining of the ependymal cells of the choroid plexus in the ventricles, as expected due to the routes of delivery into the CSF (Supplementary Figs. S3–S5) but also in areas around the frontal and mid-brain, including the hippocampal region, as well as areas around the posterior of the brain and spinal cord.”

In the paper

“The same pattern was observed for the intraventricular route (treated, DNA 90.0% cubes, control 3.9% cubes; mRNA treated 86.0% cubes, control 2.9% cubes; and protein 51.5% cubes, control 3.0% cubes; Table 3).”

In the paper

“For both the intracisternal and the intraventricular routes, for each parameter, greater than baseline levels of vector APOE2-HA copies (Fig. 2A and B), mRNA transgenes (Fig. 2C and D), and ApoE2-HA protein (Fig. 2E and F) were observed in most cubes throughout the CNS, as well as in the hippocampal regions.”

In the paper

“For the intracisternal vector-treated animals, one of three NHPs had an elevated heart rate (days 7 and 14), and one of three NHPs had an elevated respiratory rate (days 7 and 28).”

In the paper

“Pairwise statistical comparisons between the treated NHPs and non-treated sham controls showed very few parameters with significant p-values (p < 0.01), none of which had clinical significance.”

In the paper

“Similar findings lacked differences for in-life parameters (total body weight, body temperature, heart and respiratory rates; not shown), with a few scattered outliers, with nothing linked to the vector.”

In the paper

“No differences were noted for the necropsy weights between the dual-route (intraventricular plus intracisternal) and PBS-treated controls, other than smaller hearts in the smaller monkeys (not shown).”

In the paper

“When compared to the historic ranges, there were rare outlier values observed over the course of the study for a small number of hematologic and serum chemistry parameters for both treated animals and controls.”

In the paper

“Statistical comparisons between the NHP cohorts showed significance between treated and non-treated groups comparing day 28 and 56 titers for each group by the Student's t-test (total antibody titers, intracisternal vs. non-treated, p < 0.01; intraventricular vs. non-treated, p < 0.04, intracisternal vs. intraventricular, p > 0.06; Fig. 5A;”

In the paper

“neutralizing titers, intracisternal vs. non-treated, p < 0.02; intraventricular vs. non-treated, p < 0.03; intracisternal vs. intraventricular, p > 0.06; Fig. 5B).”

In the paper

“For the intracisternal vector-treated treated animals, there was a significant difference between treated and control animals for globulin (day 28) and albumin/globulin ratio (day 28). For the intraventricular vector-treated animals, there was significant difference between treated and control animals for WBCs (day 0) and reticulocytes (day 28). For the dual intraventricular/intracisternal vector”

In the paper

“For the dual intraventricular/intracisternal vector-treated animals, one of three NHPs had an elevated heart rate (days 7 and 14).”

In the paper

“No visual pathology was noted around the administration sites other than thin holes from catheters. No inflammation or pathologic abscesses were discovered on the MRI series.”

In the paper

“The data demonstrate that the direct hippocampal, intracisternal, and intraventricular routes all result in effective expression of ApoE2-HA in the hippocampal and entorhinal cortex region, the regions effected the earliest in AD,39–42 and do so safely.”

In the paper

“Both the intracisternal and intraventricular routes result not only in intrahippocampal expression, but also in widespread expression throughout the brain.”

In the paper

“The vector-administered groups did not differ from the sham control in any parameter.”

In the paper

“the intracisternal and intraventricular routes are equivalent in vector, APOE2 mRNA, and ApoE2-HA protein, and both routes are equally safe”

In the paper

“All experiments were conducted in an AAALAC-accredited facility and approved by the Institutional Animal Care and Use Committee of Weill Cornell Medical College (New York, NY).”

In the paper

“stained with H&E, and examined by a board-certified veterinary pathologist, and histopathologic changes were recorded.”

In the paper

“Samples of the CVL were taken for quality control assays that evaluated the presence of adventitious agents.”

In the paper

“The MRI and CT images were fused to generate a three-dimensional (3D) map of the brain from which the stereotaxic coordinates were determined using Brainlab iPlan Stereotaxy 3.0 software”

In the paper

“The final purified product was characterized with assays for measures of identity, potency, and purity.”

In the paper

“Samples that failed amplification were re-extracted and retested.”

In the paper

“All assays were performed with a standard curve based on a hAPOE2-HA plasmid (108–101 gc) run in triplicate.”

In the paper

“The AAVrh.10hAPOE2-HA vector was produced under current Good Manufacturing Practice conditions at the Belfer Gene Therapy Core Facility”

In the paper

“All organs were examined grossly during necropsy performed by a board-certified veterinary pathologist”

In the paper

“These findings were compatible with a needle tract used to deliver the AAV vector in the intraventricular route and comparable to that observed in PBS-treated animals (NHP-13–NHP-14; Supplementary Fig. S8A–D).”

In the paper

“All NHPs used were quarantined for a 3-month period after arrival and were deemed in good health and suitable for experimental use.”

In the paper

“All slides were evaluated by a board-certified pathologist, and observations were recorded.”

In the paper

“Matching IgG control slides were used to remove the background from the .tif images, by setting the negative controls as masks in Adobe PhotoShop.”

In the paper

“Blinded videotape analysis of NHP behavior before surgery and after administration showed no discernible neurological differences in any of the routes tested (Fig. 6).”

In the paper

“To distinguish the vector-derived APOE2 from endogenous primate APOE2 in immunohistochemical and quantitative assays, a HA peptide tag was added to the 3′ terminus of hAPOE2 vector construct (AAVrh.10hAPOE2-HA).”

In the paper

“Behaviors were scored by observers (n = 2) blinded to treatment and route from the videotape sessions”

In the paper

“Each sample was analyzed in duplicate.”

In the paper

“the requirement for invasive surgery with weeks of postoperative recovery”

In the paper

“The most common route is direct administration to the brain parenchyma (intraparenchymal route)”

In the paper

“The elevated ALT, AST, and LDH at early time points were most likely surgery and anesthesia related,51 and all of these resolved (day 56; Supplementary Fig. S11E, F, and G).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [51] Woodward RA, 1997, Contemp Top Lab Anim Sci

In the paper

“there are disadvantages, including limited vector delivery amounts and volumes, limited spread of the vector in confined space”

In the paper

“AAV4 is astrocyte and ependymal cell specific”

What the sources say

• ?Not checked — no full text of the sourcecites [70] source

In the paper

“The advantage of this route is the directed gene delivery to specific targeted brain regions.”

In the paper

“the CED strategy has associated localized trauma possible from the surgical intervention and increased pressure of fluid volume due to vector delivery in a confined space”

In the paper

“demonstrating that gene therapy with AAVrh.10hAPOE2 generates localized ApoE2 expression and secretion across width and breadth of the CNS, resulting in successful targeting the AD-associated regions”

In the paper

“it is concluded that since the intracisternal route is the least invasive, it is the choice as the best route for APOE2 gene therapy to treat APOE4 homozygotes”

In the paper

“intracisternal delivery in NHPs is safe and results in widespread expression of ApoE2, laying the framework for a clinical trial”

In the paper

“If these levels of ApoE2 can be achieved in humans, this should be therapeutic, at a minimum converting an APOE4 homozygote to an E4/E2 heterozygote.”

In the paper

“blinded videotape analysis of behavior parameters were assessed over the course of the study with all routes”

In the paper

“vector distribution following intrathecal vector administration in NHPs was improved in one study if the animal was placed in the Trendelenburg tilted position during the intrathecal infusion, which led to superior expression in the brain, especially in the brain stem”

What the sources say

• ?Not checked — no full text of the sourcecites [94] source

In the paper

“indicating that administration to the CSF via this route is sufficient and the least invasive”

In the paper

“ApoE2 is a secreted protein”

In the paper

“the loss of visual recognition is a characteristic pathology associated with AD”

What the sources say

• ?Not checked — no full text of the sourcecites [50] source