This month a lab animal will become the initial patient in the final steps in Clive Svendsen’s 15-year quest to provide the first meaningful therapy for people with ALS, also known as Lou Gehrig’s disease. If that animal and subsequent ones in this required study have good results—no side effects from the treatment—Svendsen plans to take that data to the Food and Drug Administration in November to seek approval to begin a human clinical trial.A native of England, Svendsen first started trying to merge gene therapy and stem cell therapy at Cambridge working with Parkinson’s disease. But after moving to the University of Wisconsin in 2000 and being approached by the ALS Association he switched to ALS. He has continued the work since moving to Cedars-Sinai in Los Angeles in 2010 where he receives CIRM funds to do the necessary animal tests as well as for the first human trial.
By contrast, Nanci Ryder’s voyage with ALS has only been a few short months. Since being diagnosed with the disease in August 2014 she has thrown herself into learning about it. “The only power I have ever felt over the adversity of a life threatening disease is knowledge.” She has also enlisted the help of many of the celebrity actor-clients of her public relations firm to advocate for ALS research funding, even though she knows the research may not move fast enough to help her.
A previous ALS stem cell trial shows the ups and downs faced by advocates for this stubborn fast-progressing and ultimately fatal disease. Largely conducted at the University of Michigan and Emory University that trial had provided one of the early hints of success with a potential stem cell therapy. But a subsequent larger trial did not achieve the results it was hoped it would produce.
Svendsen argues that trial has provided valuable insights, proven that you can put stem cells in the spinal cord and provides some rational as to why his team may have greater success. The Cedars team uses a different type of cell and boosts those cells’ performance with an added copy of a gene that makes a protein known to protect the type of nerves destroyed in ALS.
The earlier trial used cells from the spinal cord; Svendsen’s team uses cells from the brain’s cortex. In both cases the cells were recovered from discarded fetal tissue, but the cells from the cortex migrate better after transplantation and are more likely to spread out and have an impact on a greater area. Both teams transplant middleman cells that are part way down the path between stem cells and mature adult cells. But those stem/progenitor cells from the two teams mature into different adult nerve tissue. The ones from the spinal cord mostly become nerve cells called interneurons, while those from the cortex being used at Cedars all transform into astrocytes, the cells that protect nerves. Astrocytes have been shown to go bad in ALS and it is their malfunction that puts the body on a deadly path to paralysis.
In addition to potentially replacing the nerves’ valuable damaged support cells Svendsen hopes to boost the chances for therapeutic success by making the cells a drug delivery vehicle. The drug of choice: a growth factor called GDNF known to enhance the survival of many types of nerves. Both of the cell types used in ALS so far produce small quantities of GDNF, but the Cedars team wants to crank up that production.
That’s where the gene therapy comes into play. The Cedars team uses a modified lentivirus as a delivery vehicle to carry the GDNF gene into the stem cells. They have shown that half of the stem cells end up having copies of the gene and make the protective elixir. Once transplanted, the cells continue to pump out GDNF into the damaged area—helping the patient’s own neurons survive and function.
As Svendsen and his colleagues complete the last tests needed to get permission to test their one-two-punch cells in humans, they are already working on a key refinement. They would like to be able to regulate when and for how long the therapeutic gene is turned on—to actually make the protective protein on demand. This could be key if any side effects develop. Using a trick that other gene therapy experts have used, they plan to further modify the genetic manipulation so that the gene is only turned on in the presence of the antibiotic doxycycline. So, taking a pill could activate the gene.
After 15 years of intense effort, you can hear the excitement in Svendsen’s voice when he talks about the possibility of beginning a clinical trial later this year. He has all the additional processes in place and says, “we will begin recruiting patients the first week we have approval.”
[May is ALS Awareness month if you want to find out more about how you can help fight the disease visit the ALS Goldenwest chapter website]