Author(s): Stephen Strom PhD, Karolinska Institute
We are now working in specially-designed clean rooms and isolating and freezing the stem cells with European Medical Products Agency approved technique and procedures which will allow us to apply for full approval to treat patients with these promising stem cells. We anticipate that we will submit a full application to the medical product agency in Sweden by mid to late 2019.
A third rail of activity has begun in the laboratory. Using the newly discovered gene editing technology, we are attempting to correct the mutations in the cellular DNA that cause liver disease. We are initially focusing mainly on urea cycle defects because the disease is severe enough that the patients are frequently referred for liver transplantation. Thus, the mutation in the liver cell results in a metabolic problem that is severe and life threatening.
Also, at transplant the liver is removed and we have access to the mutant liver tissue, allowing us to isolate liver cells, analyse the genetic defect, model the disease, and attempt to correct it. Urea cycle defects, like MSUD, frequently arise from single base mutations in DNA, so investigations of gene editing for urea cycle defects would be directly relevant to MSUD and other genetic-based liver diseases. In one series of investigations, we made stem cells from the cells isolated from the mutant liver cells, identified the mutation in the patient’s cells and with gene editing technology, corrected the mutation in the DNA.
While this is exciting, in order to move this to the clinic we would need to make hepatocytes (liver cells) in culture dishes from the corrected stem cells and transplant the patient’s own, but now genetically-corrected, liver cells back into the patient. Approval from the FDA for this type of study will likely take another 3-5 years because of the possibility of tumor formation from any stem cells that do not fully become hepatocytes.
A second line of gene editing attempts to correct the mutation in the actual liver cells (not stem cells made from the liver cells like the previously described studies). With certain mutations in the urea cycle genes that we have identified, we are now able to correct 50% or more of the hepatocytes we expose to these gene editing procedures. It is expected that gene editing of the hepatocytes themselves would make it to the clinic much faster than working through the stem cell intermediate.
All of this early work with stem cells and liver cells outside of the body are directed at establishing the safety and efficacy of the gene editing procedures.
Once these are established, we will progress to a 3rd approach, where we will investigate ways to correct the genetic defect in the liver of the patient. This final approach will be designed to correct the mutation in the person’s liver by delivering gene editing tools into the blood stream where they will be delivered to the liver and correct the mutation without surgery or transplant procedures. We are working with a major Pharma company to try to move gene editing for liver diseases to the clinic within 2 years.