Finding better treatments for devastating rare diseases

February 27, 2019 | by Abe Rosenberg

City of Hope has long been renowned for its expertise in treating cancer and diabetes. But specialists here also are tackling lesser-known but equally devastating diseases that may or may not have an oncologic component. On this Rare Disease Day, we take a look at a few of them.

Canavan Disease

Imagine the anguish of a parent who learns that his child has inherited a deadly neurological disease that's so rare, hardly anyone has heard of it, let alone found a way to treat it.
City of Hope researcher Yanhong Shi, Ph.D., director of the Division of Stem Cell Biology Research, doesn't have to imagine. She hears it.
“Families call me,” she said. “And I tell myself, I must work harder.”
Shi is searching for a cure for Canavan disease, a genetic abnormality that targets the brain's white matter, or myelin, making it impossible for nerve cells to transmit messages. Babies born with Canavan disease can't crawl, walk, sit or talk. They suffer seizures, blindness and paralysis. Few survive past childhood.
Stem cell technology may offer hope. With help from grants from the California Institute for Regenerative Medicine, Shi is examining ways to genetically modify a patient's stem cells to correct the inherited defect. Lab results have shown promise. Protocols are being written for human clinical trials.
Because Canavan is a straightforward, single-gene mutation, it's also the ideal situation for testing Shi's stem cell concepts, which, if successful, could be applied to multiple sclerosis, Parkinson's, Huntington's, Alzheimer’s and other disorders.
“If it works here, we can expand it to pretty much any disease with a genetic component.”

Myelodysplastic Syndromes

With only about 13,000 new cases each year, the rare blood disorders collectively known as myelodysplastic syndromes (MDS) don't typically receive much attention.
It's different at City of Hope, and hematologist/oncologist Ryotaro Nakamura, M.D., is a big reason why.
“When I see a problem, I get engaged and I try to do something about it,” he said. “And listening to patients (with MDS) ... how they struggle with their symptoms ... I just don't want to feel helpless.”
MDS begins in the bone marrow and prevents blood cells from developing normally. Without mature, healthy blood cells, patients experience fatigue, shortness of breath, pale skin, infections, unusual bleeding, bruising and “petechiae,” or blood spots under the skin. One-third of all MDS patients develop leukemia.
No drug exists to stop or reverse MDS. A stem cell transplant is the only treatment that offers a potential cure.
But transplants require radiation or chemotherapy beforehand to clear out the old bone marrow. Many MDS patients have already gone through that, to treat various cancers. (It may be, in fact, what caused their MDS in the first place.) And it may disqualify them for a transplant.
“People who've had intensive (radiation and) chemo have leftover damage in their lungs, heart and kidneys,” Nakamura said. “They may not be able to tolerate a second round.”
Nakamura is investigating ways to lower the toxicity of pretransplant treatments. His “reduced intensity conditioning” regimens have shown that MDS can be stopped, and post-transplant complications prevented, even when smaller doses of chemo or radiation destroy only some of the original bone marrow, rather than all of it. “The outcomes are very good,” he said.

Blastic Plasmacytoid Dendritic Cell Neoplasm

Even experienced hematologists rarely see a case of blastic plasmacytoid dendritic cell neoplasm, an aggressive disease of the bone marrow and blood that can ultimately damage multiple organs.
“BPDCN is a real challenge because of its rarity and how chemo-resistant it is,” said City of Hope hematologic oncologist Elizabeth Budde, M.D., Ph.D. Patients who get chemotherapy may sometimes go into remission, but the disease almost always returns, often in a drug-resistant form.
“That's why we try to get patients onto the stem cell transplant track right away,” Budde said. “We have a long history at City of Hope with transplants, and that knowledge helps me and my colleagues provide the best care.”
And now there are new, promising alternatives for BPDCN patients who don't qualify for a transplant. One is a CAR T cell treatment called MB-102. It uses CAR T cell technology pioneered at City of Hope to target the biomarker CD123 on BPDCN cells. This experimental treatment was granted orphan drug designation by the U.S. Food and Drug Administration in December 2018.
Another recently approved drug, tagraxofusp-erzs, attacks BPDCN cells using CD123-targeted delivery of a bacterial toxin.
Budde calls both treatments “a major step forward,” though neither is expected to replace stem cell transplants anytime soon.

T Cell Lymphoma

Among the many forms of non-Hodgkin's lymphoma, T cell lymphomas are among the rarest, making up perhaps 15 percent of cases. One form, cutaneous (on the skin) TCL, is slow-growing and disfiguring but generally not fatal. Another form, peripheral TCL, can be aggressive and deadly.
As director of City of Hope's T cell Lymphoma Program, Jasmine Zain, M.D., advocates for the role of stem cell transplantation in the management of aggressive T cell lymphomas. For some patients it may provide the chance of a long-term remission and possibly a cure.
That's why Zain, part of City of Hope's Toni Stephenson Lymphoma Center team, is investigating a unique “double-teaming” strategy for prepping transplant patients.
Zain is running a clinical trial that combines traditional BEAM (a four-drug combination) chemo with a radioactive antibody called basiliximab, which has been shown in lab tests to inhibit tumor growth. The hope is that this one-two punch will improve the effectiveness of the transplant and hold off relapses.
Zain said her work benefits from City of Hope's extensive resources for trials as well as transplants. Even more important, Zain praised her patients' courage.
“I see them and their families going through horrendous times,” she said. “Yet they display such bravery, volunteering for trials even when their own situation is grim. Frankly, it's more than I think I could do in their place.”
Zain feels she owes her patients her very best.
“It's the only reason I do this.”
 
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