Molecular motors are tiny machines that move cargo from one place in a cell to another, often traveling down the length of a neuron or a muscle cell. When these machines breakdown, numerous different disorders and symptoms can occur. In the case of one, dynactin, Erika Holzbaur, PhD, professor of physiology, showed how different mutations can cause distinct disorders.

Mutations in the dynactin gene that disrupt transport throughout the neuron lead to a rare motor neuron disease called distal hereditary motor neuropathy 7B. By contrast, mutations in the dynactin gene that just disrupt the start of transport in the neuron lead to Perry syndrome, which is characterized by Parkinson's disease-like movement symptoms and psychiatric changes.

Meanwhile, Robert B. Wilson, MD, PhD, Professor of Pathology and Laboratory Medicine, has been focused on Friedreich's ataxia, a degenerative neuromuscular disorder that affects about 1 in 50,000 people in the United States. The onset of Friedreich's ataxia varies, with some individuals developing symptoms in their childhood and others only showing signs in adulthood. The earliest signs are often a loss of coordination and muscle weakness. As the disease progresses, they lose more and more muscle function and will eventually require a full-time wheelchair.

Using high-throughput screening techniques, Wilson's team screened more than 340,000 compounds in the fall of 2008 to look for potential drugs that could halt disease progression. Last year they reported early clinical trial results showing that one compound, A0001, improved neurological function in 31 patients. The drug doesn't fix all of the symptoms, but the improvements seen in the trial were good enough, according to the researchers, that longer trials are warranted to see if the improvements continue.

Wilson, though, isn't the only one getting new compounds into the clinic. H. Lee Sweeney, PhD, the first director of the Center for Orphan Disease Research and Therapy, studies Duchenne muscular dystrophy (DMD), which is a rare X-chromosome-linked disorder that affects approximately 1 in 3,600 boys. He led a team of researchers who showed that a new drug called PTC124 could override a genetic mutation causing muscle degeneration in DMD mice without causing apparent side effects. PTC124, developed by PTC Therapeutics, a small biotech firm in NJ, in collaboration with Sweeney’s lab, is currently in clinical trials with DMD and cystic fibrosis patients.

Penn Med researchers have also solved one of most perplexing medical mysteries in recent years involving a difficult-to-diagnose, rare, and potentially deadly disease that was only recently discovered. Most recently, they found that it can be controlled most effectively if treatment is started within the first month that symptoms occur. The researchers analyzed 565 cases of this recently discovered paraneoplastic condition, called Anti-NMDA Receptor Encephalitis, and determined that if initial treatments fail, second-line therapy significantly improves outcomes compared with repeating treatments or no additional treatments (76 percent versus 55 percent). The disease was first characterized by Penn's Josep Dalmau, MD, PhD, adjunct professor of Neurology, and David R. Lynch, MD, PhD, associate professor of Neurology and Pediatrics in 2007. One year later, the same investigators in collaboration with Rita Balice-Gordon, PhD, professor of Neuroscience, characterized the main syndrome and provided preliminary evidence that the antibodies have a pathogenic effect on the NR1 subunit of the NMDA receptor in Lancet Neurology in December 2008. The disease can be diagnosed using a test developed at Penn and currently available worldwide. With appropriate treatment, almost 80 percent of patients improve well and, with a recovery process that may take many months and years, can fully recover.

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