Twin disorders

Twin Disorders What can two little girls teach us about Alzheimer's disease? By Alison McCook hen you meet identical four-year old twins Addi and Cassi Hempel, you might notice something about the way they walk. They used to run around like other toddlers, but now they are more wobbly, more uncertain, and walk with their legs somewhat wide apart, as if aboard a boat. They can sway in any direction, losing their balance. They fall more often than they should.

Nov 1, 2008
Alison McCook

Twin Disorders

What can two little girls teach us about Alzheimer's disease?

By Alison McCook

hen you meet identical four-year old twins Addi and Cassi Hempel, you might notice something about the way they walk. They used to run around like other toddlers, but now they are more wobbly, more uncertain, and walk with their legs somewhat wide apart, as if aboard a boat. They can sway in any direction, losing their balance. They fall more often than they should.

They will notice you, and smile. They don't say words but they talk, a rhythmic, nonsensical babble from which a crystal-clear sound occasionally escapes: "ice cream," "paddycake," "four." Their heads have a slight bobble, and they sometimes can't angle their eyes downward, so they fall again.

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1 Neurons affected by both diseases experience dramatic accumulations of autophagic vacuoles and lysosomes, and cells affected by both disorders have enlarged endosomes, a feature seen in only a small number of disorders, says Nixon.

The similarities are strong enough that some researchers study NPC because of its link to Alzheimer's. "It is certainly one of the reasons we chose to get into Niemann Pick ourselves," Nixon says. "We are finding more and more reasons to draw similarities between lysosomal storage diseases [like NPC] in general and Alzheimer's."

When Goldstein chose to follow suit, however, he realized he knew little about the rare disease. In jumped Chris Hempel, who helped arrange one-on-one and conference phone calls between Goldstein and the NPC scientists she knows to educate him about its molecular underpinnings. "Parents were very helpful in facilitating that and moving me into this new area," Goldstein says.

He is now building an NPC neuron using human embryonic stem cell lines, which no longer express the NPC gene. "We're differentiating them now." The goal, Goldstein says, is to use the neurons to screen drug candidates. The technology doesn't exist to perform a high throughput screen using neurons, but he says that "it's not outside the realm of possibility" to use NPC neurons to test compounds flagged during HTP screens of non-neuronal cells. "We don't know how useful [an NPC neuron] will be," he says. "Personally, I think it will be incredibly useful."

In a kitchen with large windows that sometimes cloud over with smoke from nearby California wildfires, an island contains a tray piled with the plastic syringes, droppers, powders, and capsules the Hempels are using to try to arrest the girls' disease. The high-ceilinged kitchen is the center of life in the house, where Chris keeps her computer so she can check E-mail and correspond with scientists while staying connected to her household. This includes her mom and dad, who divorced decades ago but now sleep in separate rooms at the Hempels' to help out with the kids.

Mouse sympathetic neurons with two functional copies of NPC1 (upper panels) and two mutated versions (lower panels). The green represents stains from antibodies raised against NPC1. The cells were also incubated with the cholesterol binding compound, filipin (blue). In healthy cells, cholesterol is largely on the cell surface; in diseased cells, cholesterol is more widely distributed.
Used with permission of Elsevier, image supplied by Jean Vance, U of Alberta.

Sitting at the kitchen island, Chris reaches for the tray, picks up a white, plastic sheet of pills, and points to one capsule: "Each of these is roughly $200," she says, adding up to $160,000 per year for both girls to take the drug (thankfully, it's covered by insurance). The drug is the only prescription that comes with some evidence it may help NPC: Zavesca (miglustat), an inhibitor of glycosphingolipid synthesis, normally used to treat another lysosomal storage disorder, Gaucher disease.2

Chris's palms, knuckles and fingers are frequently stained orange from the curry spice curcumin. Her decision to try curcumin as a treatment for her kids came out of experiments by University of Oxford researcher Frances Platt, who Chris found through the Internet. Platt has been investigating NPC for years, and suspects that the dysfunctional NPC1 protein disrupts the regulation of calcium in the cell, and pharmacological agents that cause calcium to increase in the cytoplasm could correct this disruption. Platt and her colleagues found that curcumin could elevate cytosolic calcium; she tested it in NPC mice, and found it improved their disease. But Hempel didn't know this when she contacted Platt - she simply saw Platt was working on curcumin and NPC, and tried "begging for information" about whether curcumin could help her girls. Platt cautioned her that her research was preliminary, performed in mice, etc. But, yes, Platt conceded, maybe curcumin could help her girls.

Currently, the girls swallow twice-daily doses of powdered curcumin, which stains anything they put their mouths on, such as the nose of Cassi's favorite stuffed dog. The daily amount is 3,000 mg of curcumin and other ingredients added by the company that manufactures the supplement. It's hard to tell if anything is slowing the girls' inevitable deterioration, but there are hopeful signs: Months after her diagnosis, Cassi didn't even make eye contact, but on a sunny afternoon in July, she smiles at other people, even laughing when her sister farts. "I know how well they're walking because of the bruises," Chris Hempel says, and she believes the girls are doing better. Early evidence also suggests curcumin could help treat Alzheimer's disease.3

Platt is part of a group of researchers known as SOAR-NPC, or Support of Accelerated Research for Niemann-Pick disease type C. SOAR-NPC is managed by Collabrx, a new "virtual" biotech that facilitates collaborations between researchers. The purpose, says Smruti Vidwans, a molecular biologist-turned-drug development strategist who oversees the NPC group at Collabrx, is to find therapies faster by getting scientists to develop a targeted strategy for doing so, share ideas and data, and making sure no one doubles another's efforts. In exchange, researchers receive professional consulting and management services (such as Vidwans and Collabrx's software platform, which lets them share data and ideas remotely). They also receive funding from the Hide & Seek Foundation (which funds lysosomal diseases) and, primarily, Dana's Angels Research Trust, an NPC foundation.

Besides regular conference calls with each other and Vidwans, scientists have to be up for "real time peer review" in which they are constantly asking each other if they're doing the right studies, looking for the right outcomes, and so forth, says Jonathan Jacoby, COO of Collabrx, adding he is in "daily" contact with NPC scientists. "You discuss things as they happen within the group of researchers involved, which is actually quite different" from the normal process, says Platt.

"We are finding more and more reasons to draw similarities between lysosomal storage diseases like NPC in general and Alzheimer's." - Ralph Nixon

The Hempels, who are using some of the money they raised to fund Collabrx scientists, met at software company Netscape, a company known for publicly releasing the code of its software, and they were initially shocked to learn that scientists traditionally restrict access to their data until it's published, or meet their colleagues only at yearly conferences. Scientists "don't act like Internet startups," says Chris Hempel. "They're like, 'We'll call you in two weeks.' And we're like: No, you need to call us tomorrow!" She says she hopes the SOAR-NPC system becomes a model for other diseases.

The gait of mice with NPC (left), relative to wild-type (right). When paws are dipped in red and green paint, and mice walk along paper, affected mice show a shorter stride, and struggle to lift their paws between steps.
Source: PLOS Genetics / Matthew Scott

Last year, SOAR scientists identified more than 10 therapies to test in mice, and as of this summer, nearly all were being tested. They are already starting to think about the right combination therapy, Vidwans says. "This is probably something that wouldn't have happened without SOAR."

Twice now, Addi and Cassi Hempel have flown across the country to Bethesda, Md., to meet with Forbes (Denny) Porter, at the National Institute of Child Health and Human Development. They are part of his longitudinal trial of NPC, designed to define biomarkers researchers could use as part of a clinical trial and diagnostic test for NPC.

Chris Hempel also helped with this project. Once her kids were enrolled in Porter's trial, she asked him if there was anything she could do. Actually, there was: "I'm at the NIH, so we don't see many control kids," Porter told her. The study needed to compare blood and urine samples from NPC kids to those from healthy kids, and most kids who come through the NIH have some sort of a disease. She and another NPC parent immediately got to work on a urine and blood drive, and once Porter obtained approval from his IRB, "it took a couple of weeks" for the parents to send between 30 and 40 blood samples, and the same number of urine samples, he says. "It saved months of work and difficulty," Porter says.

NPC "is of enormous basic science interest." - Lawrence Goldstein

Ideally, any discovery that comes from the labs of Porter, Austin, Goldstein, or any of the Collabrx researchers would benefit more than the handful of NPC patients. "Our fondest hope" is that insights into how NPC works will yield insights into other disorders of cholesterol metabolism, such as Alzheimer's, and even cholesterol disorders in general, says Austin. (Nobel laureates Michael Brown and Joseph Goldstein studied severe hereditary familial hypercholesterolemia and discovered LDL receptors, which led to new ways of treating atherosclerosis.) "I think it's perfectly possible that what we discover [in NPC] will be useful to Alzheimer's disease and other neurodegenerative diseases," says Austin. "There's a long history of rare diseases shedding light on more common ones. This wouldn't be the first."

But for the most part, the only patients on Chris and Hugh Hempel's minds are Addi and Cassi. Standing in the kitchen making a quesadilla for himself and Chris, Hugh raises the idea of feeding tubes, for when the girls have trouble swallowing and could aspirate small particles of food or liquid into their lungs, putting them at risk of pneumonia. Parents obviously have to make the decision of whether or not to do it, but the responsibility of it is daunting, he says. "We're not going to get there," Chris asserts, resisting the possibility of her girls getting that sick.

Later on that day, Chris sits in front of her computer and quietly watches a video clip of a little boy with an advanced form of NPC, who doesn't move and makes no eye contact with his mother, who is talking to him off-camera. "It's heartbreaking," Chris says as the movie ends. It's impossible to imagine that her kids, who can still walk and talk, will one day be bedridden too. "That thought of kids losing their mind - I don't know," she says. "It's got to be one of the cruelest diseases on the planet for kids. And for parents, if they can't remember who you are."

Have a comment? E-mail us at References

1. J.V. Reddy et al., "Clues to neuro-degeneration in Niemann-Pick Type C disease from global gene expression profiling," PLoS ONE 1(1):e19, 2006.
2. S.D. Woodlhouse et al., "Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells," Lancet Neurol, 6:765-72, 2007.
3. N. Aynun et al., "Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease,"J Pharmacol Exp Ther, 326:196-208, 2008.