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Packard Center for ALS Research at Johns Hopkins

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ALS Alert Newsletter | November

The Nose Knows

Nasal biopsies may speed the development of new drugs to treat ALS

Sniff, sniff. Testing new drugs for neurological conditions using nasal biopsies may help researchers create new ALS therapies more quickly.

Drug development is an expensive and time-consuming process. It can take more than a decade and cost hundreds of millions of dollars to bring a new pharmaceutical to market. Many of the compounds initially screened as potential medications fail to work on the target organ system as predicted, which only increases the expense.

Developing drugs for nervous system disorders like ALS adds an additional layer of difficulty. To determine whether a compound effectively acts on the right target, researchers often test the potential drugs on cells taken from biopsies of the target. Potential drugs for ALS, then, would have to be tested on brain biopsies, which are difficult and expensive to obtain.

“One of the big hurdles in neurological drug discovery is to show the drug that works in a rat also works in a patient. The problem is that the tissue availability just isn’t there. In rats specifically bred for ALS research, it's easier to biopsy the brain to see whether a drug does what it's supposed to be doing. Brain biopsies on ALS patients are far more complicated. It's a big, big problem," said Rita Sattler, a Packard Center neuroscientist at Johns Hopkins University, who published a new study in Experimental Neurology that found a biopsy of nasal olfactory epithelium could be used to successfully test new CNS drugs for a variety of neurological diseases, including ALS.

Sniffing out a good substitute.

Rita Sattler

Rita Sattler

Sattler, along with Packard Center Director Jeffrey Rothstein, got an important insight from a scientist working on identifying molecular markers for schizophrenia. Instead of using a costly and dangerous brain biopsy, the researcher discovered that nasal olfactory epithelium cells in the upper half of the nostril contained many of the same protein targets as brain tissue. A nasal biopsy, the researchers speculated, might be a good stand-in for neural biopsies.

Sattler and Rothstein’s most recent study, published in Experimental Neurology, provides support for this hypothesis. The scientists compared the activity of thiamphenicol, a drug with known CNS activity in the nasal epithelium and brain tissue of mice, and then tested whether it would show activity in biopsied human nasal tissue. Thiamphenicol decreases extracellular levels of the neurotransmitter glutamate by stimulating the activity of an enzyme known as EAAT2/GLT-1 that essentially vacuums up surplus glutamate. Previous studies have found that ALS patients have an excess of glutamate in the spaces surrounding their neurons.

Obtaining the human nasal biopsy was easy and relatively inexpensive. “It’s a very noninvasive procedure. It takes about ten minutes max to get the tissue. It’s done under a local anesthetic, and only a very small sample is taken out,” Sattler said. Compare this to a brain biopsy, which is a risky surgical procedure.

Thirty healthy human volunteers participated in a Phase I clinical trial of thiamphenicol. Six participants received a placebo, 12 received 750 mg/day thiamphenicol, and 12 received 1500 mg/day. Before the trial started, nasal biopsies were obtained from one side of the nose. The most serious side effects of the biopsy were pain and minor bleeding from the biopsy site. After the two week trial, a second biopsy was performed on the other nostril, and a spinal tap was performed to determine how well thiamphenicol could enter the brain.

Sattler and colleagues showed that thiamphenicol worked on the nasal olfactory epithelium in the same way it worked on CNS samples. The drug stimulated EAAT2/GLT-1 to sop up glutamate in both the human and mouse nasal samples, just as it did in the mouse brain samples. EAAT2/GLT-1 in the biopsied nasal tissue didn’t show quite as much activity as it did in neural samples, which means researchers can’t always tell exactly how well the drug worked based on nasal samples alone. However, Sattler and colleagues could see that thiamphenicol did what it was supposed to do: increase the activity of EAAT2/GLT-1.

Looking forward.

The use of nasal biopsies isn’t a magic bullet for the development of drugs to treat ALS. It does, however, simplify one of the greatest tasks in bringing a new medication to market. Using the easy-to-obtain and relatively cheap samples of nasal olfactory epithelium, researchers can determine if a drug acts in humans the same way it does in cell cultures and animal studies.

“The nasal tissue is a peripheral tissue, so there’s not always a clear correlation between what we see in the biopsy and what we see in the CNS. Although we know that CNS proteins are expressed in this tissue, and they respond similarly to the drugs, we can’t really prove that what we see in the nasal tissue is really happening in the CNS. It’s not the optimal biomarker yet,” Sattler said.

Still, Sattler says, nasal biopsies could speed the development of new drugs for a variety of neurological disorders besides ALS, including Huntington’s disease and multiple sclerosis.

Carrie Arnold

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