The Tartan

Across the globe, countless babies are born with rare disorders each year. The National Human Genome Institute reports that approximately 350 million people are living with a rare genetic disorder, classified as a condition with fewer than 200,000 documented cases. About 80 percent of these rare disorders are genetic, and 95 percent of them do not have an FDA-approved treatment.

Current technologies struggle to deliver personalized medications for these conditions in a manner that is timely, cost-effective, and ethical. Research incentives often favor more widespread diseases such as cancer, with more patients and funding, leaving rare disorders largely overlooked and understudied. However, a recent study may offer a breakthrough. By using lab-grown organoids — a mini, organ-like mass of cells and tissue — researchers have found a way to accelerate the development of tailored treatments for individuals with rare genetic conditions.

The study, published in the journal Nature, was led by molecular biologist Scott Younger of the Children’s Mercy Research Institute. According to Science, he was inspired by the story of a young girl named Mila, who suffered from the rare brain disorder Batten disease. There are several types of Batten disease, but all lead to your body’s cells accumulating waste rather than disposing of it, ultimately leading to fatality. Researchers, however, were able to develop a life-saving treatment for Mila using an antisense oligonucleotide (ASO) — a strand of RNA designed to correct genetic mutations. Younger aimed to build on this approach and develop ASOs tailored for the children with rare genetic disorders at his institute. 

Younger’s approach involved transforming blood cells into induced pluripotent stem (iPS) cells — versatile cells capable of becoming the specific tissue types affected by a patient’s disease, such as brain or heart tissue. Traditionally, creating iPS cells from patient samples is costly in both time and money. In some cases, it can take up to a year to complete the process and thousands of dollars. Instead, Younger’s team devised a new chemical formula that significantly reduced this timeframe to just two or three weeks. Using this accelerated method, the researchers successfully converted blood cells from multiple patients into iPS cells, producing nearly 300 cell cultures from 12 patients over a period of six months.

With the new iPS cells, Younger’s team used more chemicals to reprogram them into specialized tissue, such as skeletal muscle cells and heart and brain organoids — small, artificially-grown tissue that mimic the functions and anatomy of its parent organ. Using these organoids, researchers could evaluate the effects of potential treatments before administering them to patients. 

In one particular case, Younger and his team used their new method to treat patients affected with Duchenne muscular dystrophy (DMD), a severe genetic disorder that leads to progressive muscle degeneration and weakness. DMD is caused by mutations in the dystrophin gene, which prevent the production of a protein needed for muscle function. Without dystrophin, muscle cells — including those in the heart — become damaged over time, leading to severe mobility issues and life-threatening cardiac complications.

To test the effectiveness of their approach, the researchers generated iPS cells from a patient with DMD and then directed them to develop into skeletal muscle cells and heart organoids. When they observed the heart organoids, they showed irregular, weak contractions, reflecting the dysfunction seen in the DMD patients they were derived from. 

The researchers then treated these organoids with an ASO therapy designed to target the patient’s genetic mutation. After treatment, the previously weak heart organoids attained a healthy rhythm. 

This new model is a major advancement in ASO testing for rare genetic disorders, but there are some limitations. Organoids, though functional, are immature versions of the actual organ they represent, and therefore may not fully replicate all their complexities. Additionally, in a lab setting, it is easy to directly expose the tissue to ASOs. However, in a human body, delivering ASOs to the right tissues may be much more complex, potentially complicating the scalability of the model. Still, it’s a promising step in the right direction, and with additional tests it may offer a faster way to evaluate personalized treatments for patients of rare genetic disorders.