How a South Dakota researcher is trying to arrest a rare disease by studying its origins. A Q&A with Sanford Research scientist Jill Weimer. 

It’s hard to fathom that a glitch in just a single gene can provoke so much damage. That’s the reality for thousands of victims of rare diseases. In the case of Batten disease, the common name for a series of inherited disorders known as neuronal ceroid lipofuscinoses or NCLs, defects in the ceroid lipofuscinosis, neuronal genes trigger a cascade of problems that interfere with a cell’s ability to recycle certain molecules.

Scientists have identified more than a dozen forms of NCLs; most of which surface in early childhood. Common symptoms for most of the forms include vision loss, seizures, delay and eventual loss of skills previously acquired, dementia, and abnormal movements. Children with Batten disease have a greatly shortened life expectancy. 

One of the leading researchers studying Batten disease is Jill Weimer PhD, a pediatrics professor at Sanford School of Medicine in South Dakota and Senior Director of Therapeutic Development at Sanford Research. Weimer’s team has been focusing on a novel complex of three proteins that mediate cargo selection and transport in developing and mature nerve fibers. Disruption in the complex appears to lead to one form of NCL.   

Dr. Weimer will be speaking about Batten disease at the 2nd Annual World Congress: Lessons Learned from Rare Disease and Personalized Medicine Approaches on September 17-18 in Boston. She recently joined us for a Q&A to talk about her research. Here are her responses.

For those who don’t know, what is Batten disease?

JW: Batten disease is a rare lysosomal storage disorder that primarily affects children. The children typically present with any combination of symptoms including early onset blindness, motor coordination problems, intellectual deficits, and ultimately premature death. There are cures currently on the market for the treatment of Batten disease.

Can you describe the progression of the variation of the disease that your group researches?

JW: There are actually around 13 different genetically distinct forms of Batten disease, and for each one the presentation of symptoms, the age of onset, and the approximate life expectancy varies. My lab has been heavily focused on CLN6 Batten disease over the last decade. In this form of the disease, patients typically present around the age of 3 to 4 with intellectual and motor deficits. As they age their motor abilities continue to decline, they start to have language deficits, they’ll have an eventual onset of seizures, they become wheelchair-bound and completely lose the ability to communicate, and usually die around their 12th birthday. It’s a horribly devastating disease with a very rapid progression.

Can you describe your role at Sanford Research?

JW: Because my work has heavily focused on therapy development over the last couple of years, I have had the opportunity to work very closely with a number of pharmaceutical and biotech companies in the search for effective treatments for Batten disease. Because of the relationships that I developed with a number of these companies and my heavy focus on fostering these outward facing relationships, my role at Sanford Research has evolved beyond just a typical scientist. I currently serve as the Senior Director for Therapeutic Development and help facilitate relationships between outside entities and scientists, while continuing to run my own research lab. Of the approximately 30 research labs at Sanford, over half of them have projects focused on rare diseases. My job is to try to help connect them with patient advocacy groups, foundations focused on their specific disease, companies that are interested in the study of those diseases or the development of therapies.

Can you give us some history on Sanford’s research into Batten’s treatments?

Sanford Research is a biomedical research institute affiliated with Sanford Health. Our healthcare organization is the largest rural, not-for-profit healthcare organization in the United States, and is headquartered in Sioux Falls, South Dakota. We have hospitals and clinics located all across the northern plains. Approximately 10 years ago our organization really started to build up our research program, taking us from about 60 scientist at the time to just shy of 300 today. With that expansion, we had a heavy focus on pediatric diseases, including research on Batten disease. Our focus on therapeutic development has always been there but it has really accelerated over the last four years. A lot of that was brought about by my partnering with a foundation based out of Southern California called the Charlotte And Gwenyth Gray Foundation that had the singular focus of developing a therapeutic treatment or cure for CLN6 Batten disease. Over the last four years, we have been able to screen nearly 20 different potential treatments. The most effective of these so far has been the development of an AAV9-CLN6 gene therapy program that we were able to accelerate through pre-clinical screening in under a year and get into a clinical trial that is currently being conducted at Nationwide Children’s Hospital in Columbus.

What are some of the most promising areas of your research for treating this disease?

JW: When we started our work with the Gray Foundation, we committed ourselves to not being singularly focused on the type of therapy that we would screen. I was brought in as the CLN6 Batten expert but the foundation was quick to surround me with a number of phenomenal scientists from around the world that really pioneered the use of gene therapy, anti-sense oligo therapies, stem cell treatments, and a number of different small molecules in pharmaceuticals for the treatment of neurological disorders.

Does gene therapy look promising for treating this disease, and if so, can you define gene therapy?

JW: Gene therapy is essentially the use of viruses to re-introduce a defective gene. So with this technology we essentially hijack the common cold virus, strip out all the bad parts that might cause an immune reaction, and use it to deliver the CLN6 gene to these patients. The clinical trial for the gene therapy is currently on-going so I can’t speak to the results, but I can tell you that in our testing of a mouse model of Batten disease we were able to completely rescue the survival of these animals, the pathology within the brain, and the behavioral deficits that are associated with the disease. I believe that this form of treatment is a very effective avenue that we should focus on not only for Batten disease, but also for its use in other rare pediatric diseases.

Can you describe some of the cutting edge technology that is being used to research treatments?

JW: In addition to the cutting edge therapy that we’re exploring, one of the most useful technologies that we started utilizing in my lab over the last four years is high content screening. A lot of folks are familiar with high throughput screening which allows you to screen thousands of different drugs in a cell based assay to narrow in on one or a handful of different drugs. High content screening is the ability to screen many different parameters in cell based assays all at once. So this allows us to either rule drugs in or out before we would take them into mouse models. This has really sped up our pipeline processing for screening drugs.

What is the role of Charles River Labs in your team’s work?

JW: Charles River has been absolutely instrumental to our work over the last couple of years. The first major role  they played in our work is allowing us to be able to do neuroimaging on our mouse model for Batten disease. In partnership with the Charles River team, we have been able to look at PET, MRI, SPEC, and CT parameters that otherwise we would not have the ability to do. More exciting is the work that we’re just starting to do with their team in looking for a biomarker scoring system for monitoring Batten disease. Biomarkers in this field have been the elusive Holy Grail for the last couple of decades; I think a lot of the limitation in the previous work has been folks focused on searching for a single biomarker. By partnering with Charles River we’re taking an innovative approach in how we examine the biomarker field that we think will really uncover a unique avenue.

What, if any, are some of the fringe benefits of this research? For example, are there other diseases that will benefit from the data generated from this work?

JW: I really feel that the model we’re developing through our partnership with Charles River can have cross application for many different pediatric diseases. In fact we hope the approach we are taking will have cross applications for all forms of Batten disease from the get-go.

If you would like to hear more about Dr. Weimer’s research, check out this video story filmed last year at the First World Congress meeting.