Year 4/NCE

Being afflicted with a chronic, progressive disease means that it never stops, it is there in the morning when you wake up and it is the last thing at night that you feel when you are falling asleep. Parkinson’s disease (PD) makes you slowly lose body functions that you once took for granted. Eating tasks become more challenging as well as chewing and swallowing, simple motor movements such as turning in bed or getting out of the car or a deep chair takes a lot of extra effort. You might also show signs of depression, anxiety, even hallucinations or just feeling indifferent towards hobbies/activities or being with loved ones. Autonomic functions are affected with lightheadedness, constipation, or urine control. You might lose your sense of smell, have changes in heart rate, and sleep problems. All these changes can occur at once or become apparent over time. Not everyone with PD is experiencing all of these symptoms. Every disease is different and the symptoms can be diverse. PD is a “designer disease” and needs a targeted approach clinically and scientifically.
In this CIRM project, we focused on the clinical and genetic variability and used gene editing technology to modify the genome at precise positions (“correct genetic mutations”) known to cause clinically and neuropathologically PD. The newly created patient-derived pluripotent stem cell lines only differ at the known positions and “off-target” modifications were excluded and we were able to experimentally show that the change in the genetic sequence is “rescuing” the cellular changes relevant for PD.
The advantage of these patient-specific cell lines are that specific genetic changes can be directly investigated without the experimental noise in control cell lines. This approach has been adopted by many laboratories in the field of disease modeling and will probably become the gold standard for stem cell modeling and drug discovery.