Inside the Lab with Nicoletta Landsberger

Nicoletta Landsberger, PhD, Professor of Molecular Biology at the University of Milan in Italy, met girls with Rett syndrome for the first time 15 years ago through a local association of families that had funded one of her grants. The meeting completely changed her approach to her research.

“The parents kept on telling me…‘we need your [research] effort for these girls’,” Landsberger recalls, “It had never happened to me before- thinking that my work could be useful for someone. Because when you are working on basic research [like I was at the time]…you are thinking it’s so cool to find out how our cells are working…but you don’t [always get to appreciate] that this is helpful to someone.”

At the time, Landsberger was studying MECP2, the gene that causes Rett syndrome. Huda Zhogbi, MD, had only recently linked MECP2 to Rett syndrome, and she and her collaborator were among the few researchers in the world who had previous experience working with it.

Landsberger had been motivated to research MECP2 simply because she was curious about what it did inside cells. However, meeting the girls and their families inspired Landsberger to dedicate the rest of her career to advancing Rett syndrome research.

This isn’t always easy for Landsberger. At times, it has meant putting aside basic discovery research projects that she was very interested in so she could focus instead on science that would help translate discoveries to patients. This translational research requires a totally different way of thinking than the basic science she was trained in. That said, she has found a way to make it work for her.

“We should never forget the importance of basic research that has to be developed in parallel with translational studies,” Landsberger says, “I [also] believe that scientists have to defend the importance of testing different approaches in order to find therapeutic solutions for RTT patients. Therapies might differ depending on age, condition, mutation, etc…”

Scouting for a New Rett Syndrome Drug Screening Method

Landsberger is always looking for ways to help patients with Rett syndrome and their families. Just a few years ago, these efforts led her to discuss International Rett Syndrome Foundation’s Scout program with Steve Kaminsky, PhD, while he was still serving as Chief Science Officer.

Kaminsky developed the Scout program to enable Rett syndrome drug development. At the time the Scout program was created, there weren’t any pharmaceutical companies investing in Rett syndrome drug development. Through the Scout program, researchers perform preclinical testing of potential Rett syndrome drugs. Doing so de-risks Rett syndrome drug development for pharmaceutical companies and makes it easier for them to sponsor clinical trials. This approach has proven effective. To date, 3 drugs have entered clinical trials thanks to the Scout program.

However, Kaminsky envisioned even better. He wanted to accelerate the process of Rett syndrome drug development further, and he knew that doing so required a new approach to preclinical testing. Testing in mouse models (such as the mouse model of Rett syndrome used for Scout program preclinical testing) is low-throughput, expensive, and time-consuming. They were really looking for a novel system that would permit them to preselect from a large amount of molecules,” Landsberger says, “This [system] should accelerate the number of molecules that will end up in clinical trials.”

Landsberger’s Novel Approach

Landsberger has a system that might serve this purpose.

As part of a previous project, her lab developed a novel cell culture system for studying neurodevelopment in Rett syndrome. Using this system, they detected differences in the genes expressed in cells from normal (“wild-type”) mice and those from a mouse model of Rett syndrome. They further showed that treating the Rett syndrome cells with a stimulus could reduce or eliminate this difference.

Landsberger believes that this system could be used to perform the high-throughput screens that Kaminsky envisioned.

Using funds recently awarded through IRSF’s Translational HeART award, Landsberger is currently putting her system to the test. Landsberger’s lab will determine if a subset of the 25,000 genes present in mice can be used to detect successful Rett syndrome treatment. If so, they will use this subset of genes as a panel to screen through a library of compounds that may contain new Rett syndrome drugs.

If successful, a standard Rett syndrome gene expression “reader” containing the gene panel will be developed. This “reader” and Landsberger’s cell culture method could provide an accessible and uniform way for Rett syndrome researchers around the globe to perform high-throughput drug screens.

This vision is only possible thanks to the research support of generous donors.

“[Our IRSF grant provides enough funding] to give us the opportunity to understand if this is a good idea or a bad idea,” Landsberger states, “This is essential [for this research], and I’m very grateful.”

Landsberger truly believes in this research. She also stresses the importance of scientists collaborating widely to create treatments for patients with Rett syndrome as quickly as possible.

“[I’ve found] that if I could do something for [the parents of children with Rett syndrome], I was more motivated,” Landsberger says, “and [the families seem to] feel less lonely knowing that someone was working with them and for them.”