Sitting at a small table on the second floor of the Ryan Veterinary Hospital of the University of Pennsylvania, Charles Vite crosses his legs and smiles gently - the warm, mild-mannered look of someone you would trust to give shots to a beloved (and terrified) family pet. "I was debating how to talk about the cats," he says.
Along with treating some of the 30,000 animals that are brought in each year to the clinic one floor below, Vite conducts somewhat unconventional research on one of same species. In a series of air-locked rooms, rows of large crates lining the walls contain kittens, most either pawing the door in greeting or sleepily sprawled on top of their siblings. Many exhibit the feline forms of inherited neurological diseases that afflict children.
It's not a subject most pet owners like to hear about, so he keeps it out of sight of his vet clinic clientele. But when researchers working with smaller mammals such as mice or rats identify a promising therapy, Vite tries it on his animals, the "bridge between mice and people." A few years ago, he inherited a colony of cats with Niemann-Pick C.
The colony, which came from a retired researcher in Colorado, began when someone, somewhere, saw a cat exhibiting strange neurological symptoms. Vite doesn't know the details, but all colonies begin the same way: Identify the disease, find the parents of the affected animal, breed them again and again, repeating the process with their offspring, and you have an ongoing supply of affected cats. Vite screens the DNA of NPC cats the day they are born; since NPC is a recessive disease, only 25% of those born are affected. He keeps some healthy heterozygous carriers of the disease for breeding or healthy controls, and adopts some out.
When he first took in the NPC colony, Vite spent his time characterizing the disease in cats, which is caused by a single base pair missense mutation similar to the most common mutation in human NPC. Entering one of the air-locked rooms, Vite immediately walks to the last crate on the right, opens the door and reaches in towards two mewing balls of fur. "C'm here," he soothes one. He plucks a grey tabby from his bed and places him gently in the middle of the floor. "This one's affected a little bit more," he says.
The 12-week-old cat's head bobbles forward and back, and his legs appear unsure, wobbly. But his curiosity is intact, and he immediately inches towards the room's edges, sniffing. NPC cats appear relatively normal until they reach five weeks, at which point they begin to develop a tremor, which worsens. "By 16 to 18 weeks of age, they're not walking any more," Vite says, scooping him up and putting him back in the crate. At 20 weeks, most become unable to lie on their chests, so they're put down.
Both cats are currently taking the drug miglustat, but it's too soon to tell if it's working - they appear in better shape than some NPC cats, and in worse shape than others. "We're a little bit hopeful," Vite says. Not all of the experiments go so well. Another trial of the neurosteroid allopregnanolone, which appeared to work in NPC mice (Nat Med,10:704-11, 2004), did little to improve nervous system function in NPC cats. Still, Vite and his team recently found "remarkable improvements" in cats with alpha-mannosidosis, another type of lysosomal storage disorder, following gene therapy. (Ann Neurol, 57:355-64, 2005). In general, research using cats has helped confirm that cells affected by NPC accumulate gangliosides and unesterified cholesterol, and link nerve cell dysfunction to neurological problems.
These pockets of good news help make up for the often unpleasant job of raising cats with terminal diseases. "Typically as a vet, your goal is to breed animals who are healthy. It goes a little against our training," he says. "You're making an animal [that] you want to be sick, and you're not sure the drug you're testing will work." Vet students, who help him care for affected cats, tell him the cats with NPC and other lysosomal storage diseases (LSDs) often disturb them. Unlike cats with cancer or other diseases, NPC cats are not in pain, but their malady is painfully obvious, which can make it difficult to observe their deterioration. Sometimes, to help his caregivers, Vite will show them a video of children with LSDs, so they see the larger purpose. That's what keeps him coming back. "The idea of contributing in some way to improve a kid's life is probably the most significant part" of his research, he says.
The benefit of Vite's work, says Frances Platt of the University of Oxford, is that it provides an animal model that has a larger-sized brain and lives longer with NPC than rodents - for instance, mice with NPC typically die at 10 weeks of age.
"With mice, you can only do so much," agrees Forbes (Denny) Porter of the National Institute of Child Health and Human Development. For instance, Vite can take samples of cats' cerebrospinal fluid to look for NPC biomarkers, something that is much more difficult in the tiny mouse. It's also easier to observe eye movement in cats than in rodents, Porter says. And once a treatment has evidence it works in both rodents and cats with NPC, "it's more likely to be 'true' in humans," he adds.
However, since it is technically difficult to obtain NPC cats, Vite's model wouldn't work as a primary screen of NPC therapies, Platt notes. Vite, she says, is carefully documenting his cats' behavior, since there are not many well-accepted, quantitative measures of cat behavior, whereas there are several for mice. "The maintenance of the cat colony and Vite's research are both extremely important in advancing our understanding of NPC and for testing therapies."