Gene therapy and gene editing methods are hot topics in the health care industry, and our community members are eager to see Dravet syndrome, a genetic disorder, treated by gene therapy. DSF is pleased to offer this explanation of the current status of genetic treatments, their approaches, and insight into what the near future holds.
First, we should all understand that the definition of gene therapy is actually quite narrow. Gene therapy refers to the insertion of normal genes into cells in place of missing or defective genes in order to correct genetic disorders. At first glance, this seems like a perfect fit for Dravet syndrome: Patients with DS have one “normal” copy of SCN1A, and one “mutated” (dysfunctional) copy of SCN1A instead of two healthy copies of SCN1A like typical individuals. This results in a condition termed haploinsufficiency: One copy does not make enough healthy sodium channels to compensate for the dysfunction of the other copy. Inserting a second normal copy of SCN1A would certainly seem an easy way to fix Dravet syndrome. Unfortunately, inserting a gene into specific populations of neurons in the brain (which is separated from the blood stream by an important blood/brain barrier to prevent infection) is neither possible nor proven safe and effective in humans yet. Further complicating this potential solution for DS is the fact that the safe and effective methods of transport in gene therapy are too small to fit SCN1A, a relatively large gene. Direct editing of the mutation in SCN1A is not possible in humans yet, either.
But all hope is not lost. While the narrow definition of gene therapy excludes treatments for Dravet syndrome at this time, there are other techniques we call “genetic approaches” that, while not altering the DNA directly, capitalize on steps in the gene-to-protein pathway cells naturally use, increasing the final protein product, which, in this case, is more functional sodium channels.
Stoke Therapeutics was the first company to publicly announce their research for a treatment for Dravet syndrome. Their treatment is called “Targeted Augmentation of Nuclear Gene Output” or TANGO, and to understand it we must first revisit the normal gene-to-protein pathway. The cell’s DNA is highly protected in the nucleus of the cell. Instead of letting cell processes potentially harm that DNA, the cell reads the DNA and creates a single-stranded RNA transcript, which it can then work with without harming the original DNA material. The cell processes that transcript, creating a “messenger” RNA (mRNA), and sends it outside of the nucleus where it is translated into the final protein product. In the case of SCN1A, that final protein is the sodium channel that will be transported to the cell’s membrane and function as a gated pore, letting sodium ions into and out of the cell as needed for electrical signal propagation. Stoke noted that the cell’s processing step is not completely efficient: Many of the transcripts (both healthy and mutated) are actually degraded in the cell instead of being made into productive mRNA. By reducing the number of transcripts that are degraded, they can increase the number of productive mRNA transcripts, and, eventually, the number of sodium channels made.
TANGO does not interfere with the DNA the way traditional gene therapy would. Instead, it uses anti-sense oligonucleotides (ASOs), which are strands of nucleic acids that are complimentary to the RNA transcript the cell created when it read the SCN1A gene. These ASOs bind to a specific sequence in the transcript and prevent the cell from degrading the transcript, resulting in an increased level of healthy mRNA strands, and, thus, more healthy sodium channels. Stoke has received Orphan Drug Designation from the US FDA and plans to initiate clinical trials in the US in the first half of 2020.
Another company, Encoded Therapeutics, is using a slightly different approach to arrive at the same solution: More healthy sodium channels. They do this not by focusing on increasing the cell’s processing efficiency, but rather by upregulating the reading of the gene in the first place. Encoded has identified a regulatory sequence in the cell’s DNA, separate from the actual SCN1A gene, that tells the cell whether or not to read SCN1A and begin the gene-to-protein process. By targeting this regulatory element with a highly specific transcription factor, they can encourage the cell to read the SCN1A gene more frequently, thus increasing the number of transcripts made and, eventually, the number of sodium channels. Encoded Therapeutics is able to fit their factor into the traditional gene therapy vector (AAV) because they are not trying to insert an entire copy of the large SCN1A gene.
DSF is excited about both approaches and will keep the community posted as Stoke and Encoded continue their preclinical research and move into the clinic.
Although gene therapy is relatively close for some diseases, its narrow definition is not close for Dravet syndrome due to the challenges of the large gene size and the location of expression within the central nervous system (CNS). However, we are extremely fortunate to be at the forefront of genetic approaches to treating epilepsy, and three factors have placed us in this incredible position: 1) SCN1A was one of the first genes associated with a distinct form of epilepsy (DS), in 2001. 2) Researchers know more about SCN1A than any other gene associated with epilepsy, due in part to the time they’ve had to study it and, in part, to the efforts of DSF to encourage this study. 3) Our patient community is one of the most organized rare disease patient communities, proven capable of supporting clinical trials despite being a rare disease, and highly engaged with each other, the research community, and the clinicians running trials that bring treatments to market.
It is an exciting time for our patients, and we are excited to help facilitate research with both Stoke and Encoded. We anticipate and welcome other companies coming forward with other approaches in the next several years.