Rare Disease Gets Big Boost from California’s Stem Cell Agency

UC Irvine’s Dr. Leslie Thompson and patient advocate Frances Saldana after the CIRM Board vote to approve funding for Huntington’s disease

If you were looking for a poster child for an unmet medical need Huntington’s disease (HD) would be high on the list. It’s a devastating disease that attacks the brain, steadily destroying the ability to control body movement and speech. It impairs thinking and often leads to dementia. It’s always fatal and there are no treatments that can stop or reverse the course of the disease. Today the Board of the California Institute for Regenerative Medicine (CIRM) voted to support a project that shows promise in changing that.

The Board voted to approve $6 million to enable Dr. Leslie Thompson and her team at the University of California, Irvine to do the late stage testing needed to apply to the US Food and Drug Administration for permission to start a clinical trial in people. The therapy involves transplanting stem cells that have been turned into neural stem cells which secrete a molecule called brain-derived neurotrophic factor (BDNF), which has been shown to promote the growth and improve the function of brain cells. The goal is to slow down the progression of this debilitating disease.

“Huntington’s disease affects around 30,000 people in the US and children born to parents with HD have a 50/50 chance of getting the disease themselves,” says Dr. Maria T. Millan, the President and CEO of CIRM. “We have supported Dr. Thompson’s work for a number of years, reflecting our commitment to helping the best science advance, and are hopeful today’s vote will take it a crucial step closer to a clinical trial.”

Another project supported by CIRM at an earlier stage of research was also given funding for a clinical trial.

The Board approved almost $12 million to support a clinical trial to help people undergoing a kidney transplant. Right now, there are around 100,000 people in the US waiting to get a kidney transplant. Even those fortunate enough to get one face a lifetime on immunosuppressive drugs to stop the body rejecting the new organ, drugs that increase the risk for infection, heart disease and diabetes.  

Dr. Everett Meyer, and his team at Stanford University, will use a combination of healthy donor stem cells and the patient’s own regulatory T cells (Tregs), to train the patient’s immune system to accept the transplanted kidney and eliminate the need for immunosuppressive drugs.

The initial group targeted in this clinical trial are people with what are called HLA-mismatched kidneys. This is where the donor and recipient do not share the same human leukocyte antigens (HLAs), proteins located on the surface of immune cells and other cells in the body. Around 50 percent of patients with HLA-mismatched transplants experience rejection of the organ.

In his application Dr. Meyer said they have a simple goal: “The goal is “one kidney for life” off drugs with safety for all patients. The overall health status of patients off immunosuppressive drugs will improve due to reduction in side effects associated with these drugs, and due to reduced graft loss afforded by tolerance induction that will prevent chronic rejection.”

Stem cell-derived blood-brain barrier gives more complete picture of Huntington’s disease

Like a sophisticated security fence, our bodies have evolved a barrier that protects the brain from potentially harmful substances in the blood but still allows the entry of essential molecules like blood sugar and oxygen. Just like in other parts of the body, the blood vessels and capillaries in the brain are lined with endothelial cells. But in the brain, these cells form extremely tight connections with each other making it nearly impossible for most things to passively squeeze through the blood vessel wall and into the brain fluid.

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Compared to blood vessels in other parts of the body, brain blood vessels form a much tighter seal to protect the brain.
Image source: Dana and Chris Reeve Foundation

Recent studies have shown defects in the brain-blood barrier are associated with neurodegenerative disorders like Huntington’s disease and as a result becomes leakier. Although the debilitating symptoms of Huntington’s disease – which include involuntary movements, severe mood swings and difficulty swallowing – are primarily due to the gradual death of specific nerve cells, this breakdown in the blood-brain barrier most likely contributes to the deterioration of the Huntington’s brain.

What hasn’t been clear is if mutations in Huntingtin, the gene that is linked to Huntington’s disease, directly impact the specialized endothelial cells within the blood-brain barrier or if these specialized cells are just innocent bystanders of the destruction that occurs as Huntington’s progresses. It’s an important question to answer. If the mutations in Huntingtin directly affect the blood-brain barrier then it could provide a bigger picture of how this incurable, fatal disease works. More importantly, it may provide new avenues for therapy development.

A UC Irvine research team got to the bottom of this question with the help of induced pluripotent stem cells (iPSCs) derived from the skin cells of individuals with Huntington’s disease. Their CIRM-funded study was published this week in Cell Reports.

In a first for a neurodegenerative disease, the researchers coaxed the Huntington’s disease iPSCs in a lab dish to become brain microvascular endothelial cells (BMECs), the specialized cells responsible for forming the blood-brain barrier. The researchers found that the Huntington’s BMECs themselves were indeed dysfunctional. Compared to BMECs derived from unaffected individuals, the Huntington’s BMECs weren’t as good at making new blood vessels, and the vessels they did make were leakier. So the Huntingtin mutation in these BMECs appears to be directly responsible for the faulty blood-brain barrier.

The team dug deeper into this new insight by looking for possible differences in gene activity between the healthy and Huntington’s BMECs. They found that the Wnt group of genes, which plays an important role in the development of the blood-brain barrier, are over active in the Huntington’s BMECs. This altered Wnt activity can explain the leaky defects. In fact, the use of a drug inhibitor of Wnt fixed the defects. Dr. Leslie Thompson, the team lead, described the significance of this finding in a press release:

“Now we know there are internal problems with blood vessels in the brain. This discovery can be used for possible future treatments to seal the leaky blood vessels themselves and to evaluate drug delivery to patients with HD.”

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Study leader, Leslie Thompson. Steve Zylius / UCI

A companion Cell Stem Cell report, also published this week, used the same iPSC-derived blood-brain barrier system. In that study, researchers at Cedars-Sinai pinpointed BMEC defects as the underlying cause of Allan-Herndon-Dudley syndrome, another neurologic condition that causes mental deficits and movement problems. Together these results really drive home the importance of studying the blood-brain barrier function in neurodegenerative disease.

Dr. Ryan Lim, the first author on the UC Irvine study, also points to a larger perspective on the implications of this work:

“These studies together demonstrate the incredible power of iPSCs to help us more fully understand human disease and identify the underlying causes of cellular processes that are altered.”