The Berlin Patient

February 22, 2015 by

Feb. 27, 2015

By Medical Discovery News

Millions of people around the world are infected with HIV, the virus that causes AIDS, but only one has ever been cured. Known as the “Berlin Patient,” Timothy Ray Brown is a 48-year-old American living in Germany. Scientists and physicians have wondered how he was cured, and some recently published studies in monkeys have provided one clue.

Brown had been HIV positive since 1995. When HIV infects the body’s cells, it integrates its genetic information into cells, making the virus a permanent part of the host’s genetic information. Brown’s HIV was held at bay by antiretroviral drugs that have made this infection survivable.  However, in 2006 he was diagnosed with acute myeloid leukemia (AML), a cancer unrelated to HIV. AML affects a group of blood cells in bone marrow called the myeloid cells. Brown underwent grueling chemotherapy that failed. In the hope of saving his life, he received two bone marrow transplants. The year of his first transplant, he stopped taking the antiretrovirals, which would normally cause a patient’s HIV levels to skyrocket.

Yet, years later, there is no sign of the virus returning. Only traces of HIV’s genetic material have been found in his blood, and those pieces are unable to replicate. The big question now is: how was this accomplished?

His treatment for AML included three different factors that could have individually or collaboratively resulted in curing his HIV infection. First, in preparation for a bone marrow transplant, a patient is treated with a combination of chemotherapy and whole body radiation to eliminate the entire immune system in preparation for receiving a new one. Second, Brown received blood stem cell transplants from a person with a defective cell surface protein, CCR5, which is what HIV uses to enter cells. People with a CCR5 mutation are resistant to HIV infection. Third, his new immune system may have eliminated the virus and remnants of his old immune system that harbored it in something called a graft versus host reaction.

In an experiment to determine how Brown was cured of HIV, scientists isolated blood stem cells from three Rhesus Macaque monkeys and put them into cold storage. They then infected those monkeys as well as three control monkeys with an engineered version of HIV. Soon after infection, all six monkeys were treated with a cocktail of drugs, and just like in humans, the levels of the virus soon declined. A few months later, the first three monkeys underwent radiation treatments to eliminate their immune systems, and then their immune systems were restored using their own stem cells from storage. Months later, the antiretroviral drugs were withheld from all six monkeys, and the virus came roaring back in five of them. One of the monkeys who underwent the stem cell transplant did not have the virus return in its blood, but it was detected in some tissues.

This experiment established that the destruction of immune system prior to bone marrow transplant was not sufficient to eliminate the virus, so the selection of bone marrow cells resistant to HIV infection and/or the graft versus host reaction may be the reason Brown was cured of HIV. Further studies are needed before we will know exactly how HIV can be cured.

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Hope for Sickle Cell

September 20, 2014 by

Sept. 19, 2014

By Medical Discovery News

While sickle cell disease has long been studied, a recent discovery revealed that the disease significantly increases the levels of a molecule called sphingosine-1-phosphate (S1P), which is generated by an enzyme called sphingosine kinase 1 (SphK1). Inhibiting the enzyme SphK1 was found to reduce the severity of sickle cell disease in mice, which will hopefully lead to new drugs that target SphK1in order to treat sickle cell disease in humans.

Sickle cell disease is caused by a change in the gene that is responsible for a type of hemoglobin, the protein molecule in red blood cells that carries oxygen. This tiny change results in hemoglobin clumping together, changing the shape of red blood cells.

The name for sickle cell disease actually comes from misshapen red blood cells. Rather than being shaped like a disk, or a donut without a whole, sickle cells are shaped like a crescent, sort of bending over on themselves. The normal shape is critical to red blood cells’ ability to easily travel through blood vessels and deliver oxygen to cells and tissues. Sickle cells become inflexible and stick to each other, blocking the flow of blood through blood vessels.

Symptoms of the disease begin to appear at about four months of age. Normally, red blood cells live for about 120 days. Sickle cells only survive 10-20 days. Although the bone marrow tries to compensate for the rapid loss of red blood cells, it cannot keep up. The disease causes pain, anemia, organ damage, and possibly infections.

Although the symptoms and their severity vary, most people with sickle cell disease will have periodic crises lasting hours or days. Symptoms include fatigue, paleness, shortness of breath, increased heart rate, jaundice, and pain. Long-term damage can occur in the spleen, eyes, and other organs, and sickle cell disease increases the risk of stroke. People who only inherit one copy of the sickle cell hemoglobin gene have a milder case of the disease than those who inherit two copies, one from each parent.

Current treatments only reduce the number and the severity of crises using hydroxyrurea, blood transfusions, pain medications, and antibiotics. As the disease advances, dialysis, kidney transplants, eye surgeries, gall bladder removal, and other treatments may be necessary. The only cure for the disease is a bone marrow transplant, which is not an option for everyone.

So it’s pretty exciting that when scientists found that levels of S1P were elevated in mice with sickle cell disease, they inhibited the enzyme SphK1 to reduce the levels of S1P. As a result, red blood cells lived longer and had less sickling. The mice also had less inflammation and tissue damage, which would reduce damage to red blood cells and prevent symptoms of the disease. When they engineered sickle cell disease mice without the gene for the enzyme SphK1 that makes S1P, again the mice had less sickling and symptoms.

How does S1P influence sickling? Apparently, it binds directly to hemoglobin and reduces its ability to collect and carry oxygen, which causes the characteristic folding of cells. S1P has other roles in the body, so it is unknown whether inhibitors to SphK1 can safely and effectively be used in humans to treat sickle cell disease.

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Half Matched Yet Perfect

March 11, 2012 by

By Medical Discovery News

Dec. 31, 2011

Half Matched Yet Perfect

Americans spend much of their time waiting. Waiting in long traffic delays, waiting in line for coffee, waiting for a call back, but not for a lifeline. Yet everyday tens of thousands of people wait for lifesaving organs and bone marrow. Sadly, most die waiting.

Researchers have developed a new procedure that virtually eliminates the wait time for people who need bone marrow transplants. Called “half-matched donors,” this procedure matches a patient with someone whose tissues are only half identical, yet it works just as well as a complete match.

Right now people with leukemia and lymphoma waiting for bone marrow must find a complete match among family members or from a national registry, but more than half never do. As they wait, their cancer progresses and spreads, and many die.

Not that long ago, half-matched, or haploidentical marrow transplants, were considered impossible because of immune system rejection. So, what changed? Immunosuppressive drugs have improved significantly. But it’s not just the drugs themselves; it’s also how they’re used to prepare a patient for marrow transplantation.

In studies at Johns Hopkins Bone Marrow Transplant Program, patients were first put though six days of chemotherapy before transplantation, just enough to suppress their immune system but not harm their organs. On the day of the procedure, half matched donors, who can be a parent, sibling or child, had their marrow extracted by needle from their hipbone. Those without a blood relative were given half-matched umbilical cord blood cells from donors.

Next, researchers injected the donor marrow into the patient and three days later administered high doses of a drug called cyclophosphamide, which re-boots the immune system. The medication kills off the patient’s immune cells but leaves the donated blood cells intact to create a new immune system that is more likely to accept its new host. The new cells also begin creating cancer-free blood cells within 20 days.

Results of these clinical trials show a one-year survival rate of 62 percent for half-identical marrow transplants and 54 percent for half-matched cord blood cells. That is essentially the same success rate for people who receive complete match transplants.

Doctors at Johns Hopkins speculate half-identical transplants work because the recipient’s immune system reacts more strongly against the cancer and lowers the chance of relapse.

In the study’s final phase, doctors will perform haploidentical transplants on nearly 400 patients.  If the results are as promising, researchers estimate that more than half of sickle cell patients, and nearly all patients with blood cancers or autoimmune disorders, will have potential matches.

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