An Orphan Disease Solution?

Insight into a translational project supported by SPARK-BIH and the Validation Fund.

This article is devoted to share a short story of two scientists, who were supported by SPARK-BIH and the Validation Fund of the Berlin Institute of Health. At the Validation Fund / SPARK-BIH our focus is not only on mentoring researchers and funding their projects, but taking the time to equip project team members with additional skills in product development, and entrepreneurial know-how. The profile below is an example of one of our supported projects.

Mitochondrial Disease Project

The project we are presenting today deals with a group of disorders, which stem from the disruption of healthy mitochondrial function known as Mitochondrial Diseases. Since 2012, professors Alessandro Prigione, and Markus Schülke have been working to combat these disorders. One of the diseases they study is “Leigh Syndrome”, a rare genetic disease that occurs in at least 1 of 40.000 live births and affects vital organs with high energy consumption such as the brain, muscles, and heart leading to their malfunction and an early death within two to three years, sometimes six to seven years.

Since drug development companies don’t spread resources uniformly across the spectrum of diseases, drug development for mitochondrial diseases is critically underfunded due to its relative rarity. With limited options to consider in their pursuit of funding research for these so called ‘orphan diseases’, Markus and Alessandro sought the assistance of SPARK-BIH who is uniquely positioned to take on challenges like this. Part of SPARK’s mandate is to support projects with an evident medical need, something this project demonstrates clearly.

To understand how and why the pair came to work together we need to rewind the clock on their careers to a very different scientific setting, the early 2000s.

At this point Alessandro had just received his MD from the University of Milan, in his native Italy. In Berlin, Markus having recently returned from a research fellowship at the Nijmegen Center for Mitochondrial disease in the Netherlands, where he was part of a team that started to decipher the genetic causes of rare mitochondrial diseases, took up a position as consultant at the Charité Department of Child Neurology. Neither were captured with traditional clinical duties for different reasons, “I preferred to concentrate on fundamental questions”, Alessandro told me of his first years in the white coat. Markus painted a more Sherlockian vision telling me, “I realized I really liked it (the new position) – you had to work much like a detective when caring for patients with rare diseases and you had to read a lot. At the time it was very difficult to find the right diagnosis because many of these diseases were only described clinically, but the pathological basis was not known”. This curiosity kept him in the lab more than on the ward, but thanks to a supporting boss at the time this was alright.

In an effort to redirect his career path Alessandro pursued his PhD, spending some of that time in the US studying mitochondrial diseases.

He threw himself into the fascinating new world that was stem cell research in the mid 2000s. Markus continued his work on rare neurological disorders becoming one of Germany’s leading specialists in this discipline while keeping an eye on the developments in the stem cell research for potential solutions in treating his patients.

The options for treatment at the time were less than life-changing. “You tell your patients that we can do genetic counselling, you can tell them the recurrence risk, but you have nothing against the disease itself.” said Markus of his earlier work. Now in the same city, Alessandro and Markus began to exchange over a shared interest in mitochondrial diseases and how they might alleviate some of that frustration. They decided to combine their experiences from working with actual patients and from stem cell research.

A major shift in this landscape came in 2006 when Dr. Shinya Yamanaka published new work outlining the ability for mature, differentiated cells to be reprogrammed to revert back to an undifferentiated state. Naturally, the two scientists were not alone in thinking that this mechanism could be used to establish models based on patient-derived cells to investigate disease mechanisms.

After some intriguing initial findings it was around this time (2012) that the pair began a more formal collaboration.

It was a nice segway into their work with SPARK-BIH. The premise was; Markus would collect patient cells and send them to Alessandro in his lab who would reprogram them into neurons. Reprogrammed, patient-derived cells were used to screen a large number of compounds for their effect on cellular disease phenotypes. The idea was that they’d hopefully find one or more compounds which coax defective patient mitochondria into completing their task successfully and thereby produce the requisite ATP. Markus described it to me as creating a “disease in a dish”. An intriguing concept to be sure, but one which requires a significant amount of money.

What they needed was help from SPARK-BIH to validate their initial results. SPARK-BIH and the validation fund proved to be an ideal match for this project who not only provided the funding necessary to pursue the idea but also paired the team with advisors crucial for the further development of the project. One of those specialists was Marc Nazaré, a seasoned medicinal chemist who helped them identify the right molecule of approved drugs.

“I think the important thing that SPARK-BIH has allowed us to do is validation. Validation is essential if you want to make a difference and really make your project become a reality,” said Alessandro of his time with SPARK-BIH.

The team first generated solid in vitro-evidence using patient-derived cells. They identified compounds that reproducibly reverted the defect in patient mitochondria. After a lot of lab work, Alessandro and Markus received approval of the parents for a compassionate use treatment for one of their identified repurposed drugs on one young seriously ill patient for whom no treatment options were available. The results of this compassionate use treatment on this one patient were much better than anticipated: Before treatment, the patient suffered from severe muscle and heart weakness. Because of respiratory failure he had to be mechanically ventilated. Upon treatment, his clinical situation improved drastically. The patient is now able to breathe on his own and visit school.


Currently, both scientists are further characterizing this repurposed drug as well as chemically related compounds to start a controlled clinical trial for the treatment of Leigh Syndrome soon.

If you’re working at Charité, MDC or BIH on a translational project that addresses a significant unmet medical need, we encourage you to apply to our next call.


SPARK-BIH is a member of the SPARK Global network