Detecting vulnerable plaque with a laser-induced whisper

A relatively new imaging technique called photoacoustic imaging or PAI detects sounds produced when laser light interacts with human tissues. Working with colleagues at Michigan State, Emory immunologist Eliver Ghosn’s lab is taking the technique to the next step to visualize immune cells within atherosclerotic plaques. The goal is to more accurately spot vulnerable plaque, or the problem areas lurking within arteries that lead to clots, and in turn heart attacks and strokes. A description Read more

Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

Weakened antibody responses to COVID-19 mRNA vaccines among most patients with multiple Read more

Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype. Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients. Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple Read more

hemophilia

Tapping evolution to improve biotech products

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

fviii_2r7e

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

Doering’s lab teamed up with Trent Spencer, PhD, director of cell and gene therapy for the Aflac Cancer and Blood Disorders Center, and Eric Gaucher, PhD, associate professor of biological sciences at Georgia Tech, who specializes in ASR. (Gaucher has also worked with Emory biochemist Eric Ortlund – related item on ASR from Gaucher)

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

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A milestone in treating hemophilia

Hematologist Pete Lollar has devoted his career to developing treatments for hemophilia A, which is caused by a lack of blood clotting factor VIII. Lollar is a professor of pediatrics in Emory School of Medicine and director of hemostasis research at Children’s Healthcare of Atlanta. Last week, Lollar was honored by Emory’s Office of Technology Transfer for setting in motion research that has progressed to a phase III clinical trial of a new product, OBI-1, a special form of factor VIII.

John "Pete" Lollar, MD

Along with this milestone came a dramatic story, described by OTT’s assistant director Cale Lennon. The first patient to enroll in the clinical trial did so in November 2010 because of what appeared to be acquired hemophilia, which led to severe uncontrolled hemorrhaging. As a result of treatment with OBI-1, developed by Lollar and his research team at Emory, the patient’s bleeding was brought under control and it saved his life. He was treated at Indiana Hemophilia and Thrombosis Center in Indianapolis.

Acquired hemophilia is a challenge for doctors to deal with because it is such a surprise. Unlike people with inherited hemophilia, those with acquired hemophilia do not have a personal or family history of bleeding episodes. Their immune systems are somehow provoked into making antibodies against their own clotting factor VIII. These antibodies also appear over time in about 30 percent of patients with inherited hemophilia who take standard clotting factors.

OBI-1, a special form of clotting factor VIII, is less of a red flag to the immune system. This allows treatment of patients who cannot benefit from standard clotting factor VIII, because of the presence of auto-antibodies.

Emory originally licensed OBI-1 to Octagen Corporation, a “homegrown” startup company founded in 1997. Octagen sublicensed the OBI-1 technology to a French biotechnology firm, Ipsen Biopharm in 1998. Over the next decade, Octagen and Ipsen pursued preclinical and initial clinical studies and completed a phase II clinical trial in 2006. Ipsen purchased the OBI-1 program outright in May 2008.

In January 2010, Ipsen developed a partnership agreement with Inspiration Biopharmaceuticals, which was founded by two businessmen whose children have hemophilia. Under the agreement’s terms, Inspiration licensed OBI-1 from Ipsen and is responsible for its clinical development, regulatory approval and commercialization.

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