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Small steps to treat neuromuscular disorder

Researchers find evidence of a genetic modifier that can improve symptoms of Spinal Muscular Atrophy

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Chris Lorson examines axons through a microscope. Lorson’s lab recently published results that showed evidence that the protein plastin 3 affects the severity of SMA. | Photo by Eleanor Hasenbeck, Bond LSC

Eleanor Hasenbeck | Bond Life Sciences Center

Two new potential treatments might improve the lives of patients living with Spinal Muscular Atrophy.

Researchers in the Lorson lab at Bond Life Sciences Center recently produced a new drug that increases the lifespans of mice with SMA, and they found evidence that an increased level of the protein plastin 3 lengthened life span and improved the animal’s nerve function.

Two genes impact Spinal Muscular Atrophy, SMN1 and SMN2. In a healthy body, SMN1 creates a protein called SMN that helps maintain motor neurons controlling muscle movement. If someone is born without SMN1, their body relies on SMN2 to produce this protein, but a small change in the SMN2 gene causes it to make much less of the protein than needed. This leads to SMA, a disorder where an individual loses motor and nervous function, often starting in childhood, over a number of years.

Although rare, sometimes siblings develop SMA, providing an unusual insight into SMA development. Discordant siblings — or siblings that both have SMA but have different severities of the disorder— suggest that other factors could contribute to SMA.

Researchers are investigating why this happens. One theory is that a “genetic modifier,” another gene or protein elsewhere in the DNA, impacts the severity of SMA. The protein plastin 3 could be this modifier.

Plastin 3 doesn’t improve the severe SMA mice, but extended the lives of mice with more mild cases of the disorder. The Lorson lab created its own SMA drug, an antisense oligonucleotide that allows SMN2 to produce a functional protein. The drug is capable of extending survival of SMA mice from approximately 13 days up to 150 days from a single treatment. The typical lifespan of a lab mouse is 1.3 to 3 years.

Kevin Kaifer, a graduate student in the Lorson lab, gave the SMA mice a low dose injection of the drug, increasing their lifespan to about 30 days. Then, they modified a gene in the mice to increase the level of plastin 3. Mice that received the drug and the plastin 3 therapy lived about 40% longer than mice that received only the drug.

Lorson said the results provide proof of concept that plastin 3 does not make more SMN, but actually decreased disease severity. The SMA mice showed improved neuromuscular junctions, the sites where nerve cells fire electrical impulses to the muscles in the body.

“That’s really where plastin 3 is designed to function, at the neuromuscular junction,” Lorson said. “So that brings the idea of plastin 3 full circle; it does not increase SMN, but it does improve the function of the nerve which is where plastin 3 is supposed to function normally.”

This discovery shows promise for a future treatment to some with the disease.

“SMA is a very broad clinical spectrum disease, so there are patients who have an incredibly severe form, and patients that don’t develop disease until adulthood,” said Chris Lorson, a Bond LSC scientist. “Perhaps one therapy is not going to address that very broad clinical spectrum, and you’re going to need to address different parts of the disease with different therapeutics.”

Despite it’s relative rarity as a disease, new treatments for SMA are hitting the market. In December, the Food and Drug Administration approved Spinraza, an antisense oligonucleotide similar to the drug the Lorson lab. But the infrequency of SMA means treatment comes at a cost: $750,000 for the first year of Spinraza and $375,000 for subsequent years. Spinraza is an FDA-designated orphan drug, meaning it’s a treatment for a disease that affects less than 200,000 people in the U.S. To incentivize research into rare diseases, The Orphan Drug Act allows pharmaceutical companies longer exclusive patent rights. Drugs that treat rare diseases that impact children, including Spinraza, can be allowed priority review, basically putting these drugs on a faster track from lab to market. Though the act has led to more research in certain diseases, it has sparked controversy as patients with no other treatment options are burdened with the resulting drugs’ high cost.

Still, it’s the first FDA approved treatment available to the 9,000 Americans living with SMA.

“I think collectively this is a very exciting time in the SMA field, whether we’re talking about SMN targeting compounds or drugs that are capable of augmenting function,” Lorson said.  “To have a rare disease that has so many shots on goals, so to speak is really exciting.”

“The SMA community is really a model for how foundations, families, patients and government agencies can come together,” Lorson said. He said families and government agencies are often in the same room as academics, biotechnology and pharmaceutical companies during meetings.

“The amount of support from the patients, the families and the non-profit world has really helped drive SMN research… I think that’s really helped push SMA from an unknown 20 years ago, to an approved drug.”

Christian Lorson is a professor of veterinary pathobiology at the Bond LSC. His research focuses on spinal muscular atrophy.
The results of this study were published in an article in JCI Insight, “Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy.” This work is partially funded by grants from the Muscular Dystrophy Association, FightSMA, the Gwendolyn Strong Foundation, and the Missouri Spinal Cord Injury/Disease Research Program. CureSMA provided the initial support for the development of the drug/antisense oligonucleotide used in these studies.

 

Old friends, new ideas

A partnership between MU and Gyeongsang National University in South Korea has created lasting connections

By Eleanor Hasenbeck | Bond Life Sciences Center

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Discussion went global this week as researchers converged from Gyeongsang National University in South Korea, MU and Washington University at Bond Life Sciences Center for the sixth MU-GNU International Joint Symposium in Plant Biotechnology.

Plant biologists from each university shared their research, ranging from molecular biology and signaling to breeding soybeans for improved yields. The symposium is held every two years, alternating locations between the U.S. and South Korea. This conference marks the eleventh year of collaboration between GNU and MU.

“Every trip that comes over, new collaborations develop,” said Gary Stacey, a Bond LSC scientist of soybean biotechnology and chair of the symposium’s local organizing committee. “Just at dinner the other night, you could hear people talking and saying ‘We should do that together.’ You get people together and they collide, and good things come from that. The whole idea of these symposiums is try to increase those collisions.”

As those involved share new research and ideas, these collaborations create opportunities. A former student in Stacey’s lab recently received a doctoral degree from both universities as part of a joint-doctoral degree program. Undergraduate Korean students can also complete a “2+2” degree, where students can begin their studies with two years at GNU and finish with two years at MU.

The schools also exchange faculty members. GNU researchers Jong Chan Hong and Woo Sik Chung completed sabbaticals at MU. Stacey has spent time in Korea, and his lab receives funding from Korean grants.

“Getting our students to interact with Korean students and Korean faculty expands their horizons, gets them in contact with other cultures and is really part of creating an intellectual environment where students can grow,” Stacey said.

For Stacey, the symposium has also brought valued friendships. “After you’ve been over there, and you know these guys for eleven years, it’s like your cousin coming home,” he said. “You’re not a visitor anymore. You’re like part of the family.”

For more information about the science exchanged, visit http://staceylab.missouri.edu/symposium.

The next Martians: the common bean?

Researchers in the Mendoza-Cozatl lab grow beans in a soil that simulates Martian soil
By Eleanor C. Hasenbeck | Bond Life Sciences

As NASA works to send people to Mars, researchers at the Mendoza-Cozatl lab at Bond Life Sciences Center are exploring the possibility of sending beans to the red planet. The journey from Earth to Mars alone would take somewhere between 100 to 300 days. To feed astronauts on these longer missions, scientists are studying space horticulture.

Norma Castro, a research associate in the lab, studies how common beans grow in a soil that simulates Mars’ red soil. The common bean is a good candidate for interstellar cultivation. Beans are a very nutritious crop, and their affinity for nitrogen-fixing bacteria can improve soil health while requiring less fertilizer. Castro is trying to understand how different varieties of beans could grow in the soil.

“This kind of research not only will tell us the right plants to take to Mars, but also which kind of technology needs to be developed,” Castro said.

Harvard researcher to speak at Life Sciences Week

Jessica Whited studies the genetics behind how salamanders grow severed limbs

By Eleanor Hasenbeck | Bond LSC

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An axolotl rests at the bottom of its tank at Menagerie du Jardin des Plantes in Paris. | photo by Jack Baker, Flickr

It takes about two months for an axolotl to regenerate a lost limb. Humans, as you probably know, don’t regenerate limbs.

But, a basic understanding of how the Mexican salamander regrows limbs advance regenerative medicine in humans according to Jessica Whited, a researcher at Brigham Women’s Hospital and assistant professor at Harvard Medical School.

Whited will speak at 3:30 p.m., Thursday April 13, in Monsanto Auditorium as part of Missouri Life Sciences Week at Bond Life Science Center. Her lecture, “Identifying roadblocks to regeneration in axolotl salamanders” will present the lab’s discoveries and evidence that a specific gene in axolotls can block the animal’s ability to regenerate.

Whited’s lab found axolotls can exhaust their ability to regenerate. When a limb is severed repeatedly, the salamander stops producing blastemas, the mass of cells capable of regeneration that allow the limb to grow back. This could be due to a dysregulated gene blocking the animal’s ability to produce them.

The Whited Lab sequenced the mRNA in axolotls that could regenerate limbs and that could no longer regenerate. They found 912 genes that differed between the two groups. Whited will discuss one of these genes, which her lab considers a potential inhibitor to regeneration.

“It’s much more common for people to think “Oh, what are the things that promote limb regeneration?’ than it is to think about the things that we might have to block to make it happen,” Whited said. “This project has the potential to uncover the roadblocks, which could turn out to be equally critical.”

An MU alumna, Whited received the National Institutes of Health New Innovator Award in 2015 for her work with this unique regenerative salamander. She earned a PhD in biology at the Massachusetts Institute of Technology, and two undergraduate degrees in biological sciences and philosophy at MU.

Whited attended MU as a Bright Flight and Curator’s Scholar. And though it happened nearly 20 years ago, she said receiving those two scholarships were among the most important things that happened in her career. As a high school student, she knew she would go to college, but financially, she didn’t know how it would happen. She also credits her education and undergraduate research experience at MU for preparing her to think at the research bench.

“You have to get an undergraduate education, and it totally prepared me even for graduate school at MIT, which is one of the top programs in the world, in many subjects, but in biology especially,” Whited said. “The idea that you could find a career where you’re using your brain as your primary asset, I figured that out while I was at the University of Missouri, because there were people, our professors, doing that.”

Whited’s lecture is free and open to the public as part of Missouri Life Sciences Week. It occurs at 3:30 on Thursday, April 13 in Bond LSC’s Monsanto Auditorium. See more about events during the week at bondlsc.missouri.edu/life-sciences-week.