Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase.

Immune responses to human non-self transgenes can present challenges in preclinical studies of adeno-associated virus (AAV) gene therapy candidates in nonhuman primates. Although anti-transgene immune responses are usually mild and non-adverse, they can confound pharmacological readouts and complicate translation of results between species. We developed a gene therapy candidate for Pompe disease consisting of AAVhu68, a clade F AAV closely related to AAV9, that expresses an engineered human acid-alpha glucosidase (hGAA) tagged with an insulin-like growth factor 2 variant (vIGF2) peptide for enhanced cell uptake. Rhesus macaques were administered an intravenous dose of 1x1013 genome copies (GC)/kg, 5x1013 GC/kg, or 1 x 1014 GC/kg of AAVhu68.vIGF2.hGAA. Some unusually severe adaptive immune responses to hGAA presented, albeit with a high degree of variability between animals. Anti-hGAA responses ranged from absent to severe cytotoxic T-cell-mediated myocarditis with elevated troponin I levels. Cardiac toxicity was not dose dependent and affected five out of eleven animals. Upon further investigation, we identified an association between toxicity and a major histocompatibility complex class I haplotype (Mamu-A002.01) in three of these animals. An immunodominant peptide located in the C-terminal region of hGAA was subsequently identified via enzyme-linked immunospot epitope mapping. Another notable observation in this preclinical safety study cohort pertained to the achievement of robust and safe gene transfer upon intravenous administration of 5x1013 GC/kg in one animal with a low pre-existing neutralizing anti-capsid antibodies titer (1:20). Collectively, these findings may have significant implications for gene therapy inclusion criteria.

A Tablet-Based Tool for Accurate Measurement of Hand Proprioception After Stroke.

BACKGROUND AND PURPOSE: Proprioceptive deficits in the hand are common following stroke, but current clinical measurement techniques are too imprecise to detect subtle impairments or small changes. We developed a tablet-based tool to measure static hand proprioception using an adaptive staircase procedure. METHODS: In 16 individuals with chronic stroke and age-matched controls, we quantified proprioception at the metacarpophalangeal joint of the index finger using 3 methods: the tablet task, a custom passive movement direction discrimination test (PMDD), and a manual assessment similar to the Fugl-Meyer (F-M) proprioception subsection. RESULTS: The tablet-based measure and the PMDD both identified impaired proprioception in the affected hand relative to the unaffected hand (P = 0.024 and 0.028), and relative to the control group (P = 0.040 and 0.032), while manual assessment did not. The PMDD had a ceiling effect as movement excursions greater than 15 were not biomechanically feasible. The tablet-based measure and the PMDD detected impaired proprioception in 56% to 75%, and the F-M in only 29%, of patients. PMDD and tablet-based measures were both correlated with primary tactile sensation, but not manual dexterity. DISCUSSION AND CONCLUSIONS: Both the tablet-based tool and the custom PMDD performed better than manual assessment. The PMDD may be useful when the deficit is mild or assessment of dynamic proprioception is desired. As the tablet-based measure does not have the ceiling effect that is associated with the PMDD, it may be useful with any level of proprioceptive impairment, and may be preferable if testing or clinician training time needs to be minimized, or pain or spasticity is present.Video Abstract available for more insights from the authors (see the Video, Supplementary Digital Content 1, available at: http://links.lww.com/JNPT/A256).

Culturally Relevant Palliative and End-of-Life Care for U.S. Indigenous Populations: An Integrative Review.

PURPOSE: American Indians/Alaska Natives (AIs/ANs) have higher rates of chronic illness and lack access to palliative/end-of-life (EOL) care. This integrative review ascertained the state of the science on culturally acceptable palliative/EOL care options for Indigenous persons in the United States. DESIGN: Databases searched: CINAHL, PubMed/MEDLINE, SocINDEX, PsycINFO, PsycARTICLES, ERIC, Health Source: Nursing/Academic Edition, and EBSCO Discovery Service 1880s-Present. Key terms used: palliative care, EOL care, and AI/AN. INCLUSION CRITERIA: peer-reviewed articles published in English. Findings/Results: Twenty-nine articles were identified, 17 remained that described culturally specific palliative/EOL care for AIs/ANs. Synthesis revealed four themes: Communication, Cultural Awareness/Sensitivity, Community Guidance for Palliative/EOL Care Programs, Barriers and two subthemes: Trust/Respect and Mistrust. DISCUSSION/CONCLUSION: Limitations are lack of research funding, geographic isolation, and stringent government requirements. Palliative/EOL care must draw on a different set of skills that honor care beyond cure provided in a culturally sensitive manner.

Modality-specific Changes in Motor Cortex Excitability After Visuo-proprioceptive Realignment.

Spatial realignment of visual and proprioceptive estimates of hand position is necessary both to keep the estimates in register over time and to compensate for sensory perturbations. Such realignment affects perceived hand position, which the brain must use to plan hand movements. We would therefore expect visuo-proprioceptive realignment to affect the motor system at some level, but the physiological basis of this interaction is unknown. Here, we asked whether activity in primary motor cortex (M1), a well-known substrate of motor control, shows evidence of change after visuo-proprioceptive realignment. In two sessions each, 32 healthy adults experienced spatially misaligned or veridical visual and proprioceptive information about their static left index finger. Participants indicated perceived finger position with no performance feedback or knowledge of results. Using TMS over the M1 representation of the misaligned finger, we found no average difference between sessions. However, regression analysis indicated that, in the misaligned session only, proprioceptive realignment was linked with a decrease in M1 activity and visual realignment was linked with an increase in M1 activity. Proprioceptive and visual realignment were inversely related to each other. These results suggest that visuo-proprioceptive realignment does indeed have a physiological impact on the motor system. The lack of a between-session mean difference in M1 activity suggests that the basis of the effect is not the multisensory realignment computation itself, independent of modality. Rather, the changes in M1 are consistent with a modality-specific neural mechanism, such as modulation of somatosensory cortex or dorsal stream visual areas that impact M1.