Week in Review: Number 5

A Cytoplasmic Self-Priming Retrotransposon
This news article by The Scientist is a follow up to articles about Jayakrishna Ambati's research into NRTIs as a potential therapeutic for atrophic AMD. The article approaches the research with a focus on cytoplasmic DNA. This finding in itself is novel to basic science. In particular, Alu is an endogenous retrotransposon found in the human genome, but its presence and reverse transcription in the cytoplasm rather than in the nucleus of cells was unexpected. After all, most DNA synthesis requires the transcription "equipment," such as a primer, normally located in the cell's nucleus. After investigating the sequence and RNA structure of Alu, Ambati's latest study (part of a decade of research into this topic) found that this retrotransposon could undergo self-priming. If the presence of Alu elements in the cytoplasm wasn't surprising enough, the fact that Alu is self-priming was an additional novel finding given that there is only one other RNA molecule, from a rodent gene, shown to self-prime; however, the other gene is not found in the cytoplasm. Alu is the first retrotrotransposon known to initiate its own reverse transcription, and does so in the cell's cytoplasm. Unfortunately, the fact that this retrotransposon exists in the cytoplasm is related to a disease state, triggering inflammation that eventually leads to many age-related diseases, such as macular degeneration in this case. Nucleoside reverse transcriptase inhibitors (NRTIs), drugs FDA approved for the treatment of HIV, were discussed previously for their potential to be repurposed for the treatment of diseases due to the inflammasome. In earlier research, Ambati's team showed that NRTIs have an anti-inflammatory effect. In the most recent study, the researchers showed that NRTIs have an additional effect of inhibiting transcription of cytoplasmic Alu.

Investigating Coupled Immunomodulation in the Eye
Researchers at the Wyss Institute at Harvard University are investigating a new generation of adeno-associated virus (AAV) vectors for the delivery of gene therapy. This research is relevant to eye care in the sense that the eye is a prime testbed for gene therapies. Though the eye is considered immune-privileged due to the blood-retina barrier, several clinical trials have reported intraocular inflammation following delivery of therapeutically relevant doses of AAV into the eye. The more ideal delivery of AAV vectors is intravitreally, compared to subretinally, though intravitreal injection results in more inflammation. The new generation of AAV vectors incorporates “inflammation-inhibiting oligonucleotide” (IO) sequences to address this obstacle. Results of intravitreal injection in mice showed that the incorporation of IO sequences reduced inflammation and produced a multifold increase in expression of the vector-encoded gene in the retina. Similarly, subretinal injection in pigs "ameliorated distinct pathologies triggered by control AAV viruses" and reversed infiltration of immune cells into the photoreceptor layer of the retina. Studies of intravitreal injection in macaque monkeys, however, did not produce as pronounced results, though there was delay of onset of inflammation (uveitis) and mild improvement in expression of the therapeutic gene. As with any new therapy, these kinds of investigations are necessary to guide future directions toward improved safety and efficacy of gene therapies.

RPE Dysfunction in Batten Disease
Juvenile neuronal ceroid lipofuscinosis (JNCL) or CLN3-Batten disease is a rare autosomal recessive retinal degenerative disease caused by mutations to the CLN3 gene. Children missing this gene on chromosome 16 are unable to produce certain proteins necessary for cellular function of the photoreceptors, and eventually also develop cognitive and neuromuscular decline. Many individuals with Batten disease do not survive past their third decade of life. Batten disease has been challenging to study and diagnose. Because visual problems present much earlier than neurological problems, children with Batten disease are often misdiagnosed with more common retinal diseases. Furthermore, mouse models of the CLN3 gene mutation do not produce the retinal degeneration or vision loss found in humans, and examination of eye tissues post-mortem reveal extensive damage that make it difficult to determine the precise mechanism that lead to vision loss. Researchers at the University of Rochester Batten Center recently made progress in the study of this disease through human-induced pluripotent stem cells (iPSCs) engineered from the skin cells of patients and unaffected family members, which then were used to create retinal cells possessing the CLN3 mutation. Perhaps not unexpectedly, the new research revealed that proper function of CLN3 is necessary for retinal pigment epithelium (RPE) cellular structure. By locating the mechanism of Batten disease at the RPE, research into this very rare eye disease could both inform and benefit from advances in research into other retinal diseases caused by RPE dysfunction.

Small Study Investigates Automatic Object Discrimination without Visual Attention
Studies into vision science are notoriously difficult to extrapolate data from due to the complexity of neural processing. In this study, junior researchers at HSE University in Russia sought to determine whether our visual system parses spatially mixed objects of different categories automatically or whether such parsing requires attention. For example, when we look at an apple tree, we easily differentiate the apples from the leaves, but how much attention is involved? Intuitively, it makes sense that much of visual processing would be automatic, given the wealth of visual input and the bottlenecks of conscious attention. The present experiment investigated this hypothesis by loading participants' attention with a central task (such as looking at a cross) while unattended background visual stimuli (such as lines of various lengths and orientations) changed. Markers of automatic sensory discrimination were measured by visual mismatch negativity (vMMN) via electroencephalography (EEG). What can be extrapolated from vMMN results, such as multiple peaks indicating category separation, is beyond the scope of this review. A major limitation of the study, however, is its exceedingly small sample size of only 20 participants; nonetheless, the conclusion that object discrimination can occur without attention is not surprising.

Spontaneous Blink Rate and Cognitive Function
This study from the University of Tsukuba in Japan takes a neuroscience approach to the association between aerobic fitness and cognitive function through spontaneous eye blink rate (sEBR). Using blink rate as a "missing link" is possible because both sEBRs and physical activity are controlled by the dopaminergic system. Previous researchers had proposed that exercise-induced changes in cognitive function might be mediated by activity in the dopaminergic system. The present study sought to test that hypothesis through a measurable activity, in this case blink rate. The sample size of 35 participants is very small, though the researchers note that "As expected, we found significant correlations between aerobic fitness, cognitive function, and sEBR." The summary of the study is that aerobic activity and cognitive function are correlated, and both are correlated with spontaneous eye blink rate, which serves as a convenient noninvasive measure of dopaminergic activity common to both blinking and aerobic activity. The researchers hope to provide new directions to improve cognitive function through exercise. Peripherally relevant to eye care is the fact that yet another measure of cognitive function can be assessed through the eyes.

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