Quinn Eastman

Gene editing reverses Huntington’s in mouse model

Disrupting a problematic gene in brain cells can reverse Huntington’s disease pathology and motor symptoms in a mouse model of the inherited neurological disorder, Emory scientists report.

The researchers used CRISPR/Cas9 gene editing, delivered by a viral vector, to snip part of a gene producing toxic protein aggregates in the brains of 9-month old mice. Weeks later, where the vector was applied, aggregated proteins had almost disappeared. In addition, the motor abilities of the mice had improved, although not to the level of control mice.

The results were published June 19, 2017 in Journal of Clinical InvestigationEncouraging Tweet from Scripps MD/author Eric Topol.

The findings open up an avenue for treating Huntington’s as well as other inherited neurodegenerative diseases, although more testing of safety and long-term effects is needed, says senior author Xiao-Jiang Li, MD, PhD, distinguished professor of human genetics at Emory University School of Medicine.

Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin or mHTT) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline.

Touted widely for its potential, CRISPR/Cas9 gene editing has not been used to treat any neurodegenerative disease in humans. Several concerns need to be addressed before its use, such as effective delivery and the safety of tinkering with DNA in brain cells. A similar approach, but using a different technology (zinc finger nucleases), was reported for Huntington’s disease in 2012.  Read more

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Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

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Mitochondrial blindness — Newman’s Emory story

Neuro-ophthalmologist Nancy Newman’s 2017 Dean’s Distinguished Faculty Lecture and Award were unexpectedly timely. Her talk on Tuesday was a tour of her career and mitochondrial disorders affecting vision, culminating in a description of gene therapy clinical trials for the treatment of Leber’s hereditary optic neuropathy.

The sponsor of those studies, Gensight Biologics, recently presented preliminary data on a previous study of their gene therapy at the American Academy of Neurology meeting in April. Two larger trials (REVERSE and RESCUE) are ongoing.

Despite all the progress, there are still several puzzles connected with mitochondrial diseases affecting vision and particularly Leber’s, the first human disease linked to mitochondrial DNA mutations by Douglas Wallace at Emory in the 1980s.

Newman called Leber’s an “ideal laboratory” for studying mitochondrial diseases of vision, because deterioration of vision in Leber’s tends to happen to one eye first, presenting a window of opportunity to deliver treatment to the other eye. Read more

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IMSD program nurtures young scientists

Guest post from Megan McCall, who works at Winship Cancer Institute. Thanks Megan!

On a Thursday afternoon this past semester, a diverse group of 50 students were listening to a lecture on the art of storytelling by Eladio Abreu, a lecturer in the Biology department. This was an unusual topic for these students, but they sat enrapt, not distracted by cell phones or laptops.

Eladio Abreu, PhD

The weekly seminar was part of the Emory Initiative to Maximize Student Development (IMSD) program, aimed at the professional development of undergraduate and graduate students in STEM fields. What sets this program apart is its commitment to increase diversity in the biological, biomedical and behavioral sciences by nurturing students who may be underrepresented in these fields. IMSD’s associate director Amanda James says the program includes some of Emory’s strongest students.

The two-year, NIH-funded research program has three main goals: preparing undergraduate students for doctoral programs in STEM fields, nurturing graduate students during their matriculation into Emory’s Ph.D. programs and increasing diversity through mentoring. They accomplish these goals by connecting undergraduates and graduates through mentorship, seminars, and career coaching, says Keith Wilkinson, IMSD director and vice-chair of the Department of Biochemistry.

(from left) Lina Jowhar, Max Cornely, Chayla Vazquez, and Jamie Guillen at an Initiative to Maximize Student development meeting.

This meeting included updates from students on their summer research plans. Answers ranged from epidemiology research with a children’s hospital in Philadelphia, to influenza research at Johns Hopkins. In addition to weekly seminars, IMSD offers classes aimed at increasing success post-graduation, workshops for career development, and pathways to funded research, a rare commodity for undergraduates. Students who can’t do funded research may use resources that IMSD offers to find other opportunities.

Lina Jowhar is an undergraduate who started the program in her third year at Emory. She is engaged in research on cystic fibrosis, a genetic disorder of the lungs, and she values the weekly meetings, particularly Abreu’s lecture on the art of storytelling. “I love his interactive teaching style,” she says. “He was comfortable letting us know that he changed the examples in his PowerPoint to include Biggie and Tupac which showed me how important it is to connect with your audience.” Read more

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Flu meeting at Emory next week

We are looking forward to the “Immunology and Evolution of Influenza” symposium next week (Thursday the 25th and Friday the 26th).

The symposium is taking place in Whitehead Auditorium in the Whitehead Biomedical Research Building. Talks from flu researchers based around the country, followed by a poster session, are on Thursday. From Emory, Jacob Kohlmeier and Rafi Ahmed are speaking Friday morning.

Organizers are asking for registration by Friday the 19th. The symposium is jointly sponsored by the Center for Inference and Dynamics of Infectious Diseases, funded by NIGMS, and the Center for Modeling Immunity to Influenza Infection, funded by NIAID.

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NGLY1 update

Emory Medicine readers may remember the Stinchcombs, a Georgia family caring for two daughters with a genetic neurological/developmental disorder called NGLY1 deficiency. We found their efforts to care for their daughters inspiring.

The rapid discovery of several children with NGLY1 deficiency, facilitated by social media, has led to a wave of research. Two recent papers represent advances toward finding treatments.

In PLOS Genetics, Japanese scientists showed that deleting the ENGase gene can partially rescue problems created by NGLY1 deficiency in a mouse model (RIKEN press release). That implies drugs that inhibit the ENGase enzyme might have similar positive effects.

Scientists knew that the NGLY1 enzyme removes chains of sugars from misfolded proteins that are stalled in cells’ production pipeline. ENGase is another enzyme that acts on those sugar chains, and its absence compensates for the lack of NGLY1. Read more

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Amyloid vs tau? With this AD target, no need to choose

Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.

Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.

In mice, inhibiting AEP hits two targets (amyloid and tau) with one shot

Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.

That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.

Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart. Read more

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Invasive lung cancer cells have distinct roles

When cancer cells split off from a tumor to seed deadly metastases, they are thought to travel as clusters or packs, a phenomenon known as collective invasion. The members of an invasive pack are not all alike, scientists at Winship Cancer Institute of Emory University have learned.

Lung cancer cells making up an invasive pack have specialized roles as leaders and followers, which depend on each other for mobility and survival, the scientists report in Nature Communications.

The differences between leaders and followers — and their interdependence — could be keys for future treatments aimed at impairing or preventing cancer metastasis, says senior author Adam Marcus, PhD, associate professor of hematology and medical oncology at Winship Cancer Institute and Emory University School of Medicine.

“We’re finding that leader and follower cells have a symbiotic relationship and depend on each for survival and invasion,” he says. “Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship.”

Marcus and former graduate student Jessica Konen, PhD began by observing how a mass of lung cancer cells behaves when embedded in a 3-D protein gel. The cells generally stick together, but occasionally, a few cells extend out of the mass like tentacles, with the leader cell at the tip.

“We saw that when the leader cell became detached or died unexpectedly, the followers could no longer move,” says Konen, now a postdoctoral fellow at MD Anderson. “In one particular movie, we saw a leader cell come out away from the rest of the cells, and then seem to realize that nobody was following him. He actually did a 180, and went back to grab cells to bring with him.” Read more

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More pieces in Parkinson’s puzzle: VMAT2 and SV2C

The drug target VMAT2 has appeared in biomedical news lately because of a pair of FDA approvals. One medicine treats the iatrogenic movement disorder tardive dyskinesia, the first approved to do so, and the other is for symptoms of Huntington’s disease.

Gary Miller, PhD

When Emory folks see VMAT2, they should think of two things: the neurotransmitter dopamine, and Parkinson’s research conducted by Gary Miller and his colleagues. They have made a case that activators of VMAT2 would be beneficial in Parkinson’s, but the drugs in the news were inhibitors, and presumably would make Parkinson’s worse.

VMAT2 (vesicular monoamine transporter 2) is responsible for transporting dopamine into synaptic vesicles, tiny packages for delivery. As Miller’s lab has shown, mice deficient in VMAT2 can be a model for the non-motor and motor aspects of Parkinson’s. In these mice, not only are certain nervous system functions impaired, but the dopamine packaging problem inflicts damage on the neurons.

Miller’s more recent work on a related molecule called SV2C is puzzling, but intriguing. The gene encoding SV2C had attracted attention because of its connection to the striking ability of cigarette smoking to reduce Parkinson’s risk, possibly mediated by nicotine’s effect on dopamine in the brain.

I say puzzling because SV2C’s role in brain cells can’t be described as easily as VMAT2’s. Read more

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Worm collaboration w/Oglethorpe probes neurodegeneration

Emory cell biologist David Katz’s lab has facilitated a collaboration with our neighbors at Oglethorpe University, working with undergraduates on the worm C. elegans and contributing to Alzheimer’s/frontotemporal dementia research. A new article from Oglethorpe describes how C. elegans is ideal for undergraduate biology instruction. Check it out.  

In the photo: Oglethorpe student and Katz lab intern Caitlin May, Oglethorpe biology professor Karen Schmeichel, Elias Castro — also an Oglethorpe student and Katz lab intern, Katz lab postdoc Teresa Lee and David Katz.

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