Welcome back to the Cripple Command Center or C-to-the-3 podcast on ericvalor.org. My name is Eric Valor and I will be your host and head nerd in charge. In this episode I will report on a recent webinar given by CIRM, the California Institute of Regenerative Medicine, and a particular clinical trial discussed therein. I will also report on a new potential treatment target for ALS found using CRISPR, a new proposed treatment for SOD1-linked ALS, a new open-label trial for a form of curcumin, and a new stem cell model to assess possible treatments for neurodegenerative diseases such as ALS.
The first item up for bids is the new CRISPR study. Researchers at Stanford University have used CRISPR/Cas9 gene editing technology to gain insight into the genetic basis of ALS. The team, led by Doctor Aaron Gitler, used the technology to sift through the entire human genome to find genes that help neurons defend against toxic protein aggregation. In ALS it is known that proteins inside the motor neurons clump together, depriving the cell of the beneficial function of these proteins as well as choking the machinery which normally breaks down malformed or deficient proteins for recycling by the cell. The Stanford team used CRISPR to sequentially alter genes which either help cells cope with protein aggregation or enhance the toxicity. They ceased the function of each gene one by one in what’s called a “genetic knock-out” and evaluated the effect. That way they can identity potential drug targets for future therapies. You can read more about this in the Stanford News Center website. You can read the paper in Nature Genetics.
Our next item is the CIRM webinar and the upcoming clinical trial described therein. The webinar was held on Facebook. It was an “Ask The Experts” format where information is presented and then questions are asked by people watching the webinar online. The presentation was made by Doctors Clive Svendsen, Bob Baloh, and Ralph Kern. First, a little information was shared first about the NurOwn therapy in trial by Brainstorm. The Phase 3 trial is enrolling 300 people with enrollment expected to finish by early 2019. The protocol is repeat injections of the person’s own mesenchymal stromal cells which reduce local inflammation and secrete trophic factors which help the motor neurons heal and grow.
The juiciest part of the webinar was the presentation of the new Phase 1 clinical trial being prepared by Cedars-Sinai in Los Angeles. This trial is similar to the old Neuralstem trial using human fetal brain-derived neural progenitors which are multi-potent stem cells which can only become cells of neural lineage (neurons, astrocytes, microglia, etc.). In contrast to the Neuralstem product where the cells mostly became interneurons these cells become astrocytes which would replace the native astrocytes which become toxic in ALS. The cells are transduced using GDNF (glial-derived neurotrophic factor).
Cedars also uses a new method called “chopping” (which when you read the paper on the method should really be called “slicing”) to expand the cell line into a pharmaceutically-relevant number. A clump of neural cells called a neurosphere is repeatedly sliced up and the parts allowed to expand. The usual method is to break apart the neurosphere by hand and individually plate the cells. Chopping is much faster and increases yield by allowing the cells to be cultured in 3D rather than in 2D. This means the cells have more contact with others which promotes health and growth. Instead of having cells just on the left and right and on top and bottom, they also have cells above and below. Like penguins grouping together tightly in a snowstorm the cells fare much better in a 3D arrangement as in the body. Like the Neuralstem trial the Cedars trial uses a laminectomy to inject the cells into the spine but uses a new rig which is significantly less invasive. The patients undergo a year of immunosuppression to ensure the body doesn’t reject the implants. After that the cells are expected to survive for life.
Next up is the new clinical trial for the spice curcumin being put together by my friend and ALS Untangled colleague Doctor Richard Bedlack. The trial is called ROAR for Replication Of ALS Reversals. ROAR is open-label with no placebo and is designed to have faster enrollment with much better retention, and wide inclusion criteria like no 2-year cutoff or many of the other exclusions found in usual trials. That’s not to say that the usual trial design is “bad” but ROAR is looking for a huge unmistakable signal: A reversal of ALS such as regaining use of limbs or getting out of a wheelchair (the latter being a more extreme example). The trial will also have few/no in-person visits. ROAR will use a particular product called Theracumin which is a highly concentrated form of curcumin which is readily absorbed, properly metabolized, and is well-tolerated even in high doses. Trial participation for each person is 6 months. The real-time results will be available on Patients Like Me and the full protocol will be made available on www.alsreversals.org should anyone not in the trial want to follow along.
Why curcumin? Because it’s generally regarded as safe and is inexpensive to obtain. There are some 12,000 published papers studying curcumin’s effects. Curcumin has powerful antioxidant effects, can reduce protein aggregation in cells, can induce beneficial gene activation, and can alter the gut microbiome, the vast population of bacteria in the stomach and intestines, in ways that are beneficial to health including the brain and nervous system (seriously!). In mouse neuroblastoma cells transfected with mutant TDP43, curcumin improved excitotoxicity, improvd mitochondrial function, and reduced oxidative stress and protein aggregation. Unfortunately these studies have not been independently replicated. You can learn more about curcumin and prior data as relates to ALS in the ALS Untangled report on the subject and by watching the video presentation Dr. Bedlack gave on the ROAR trial.
Alrighty, what do we have next? Ah, yes, the new stem cell model meant to assess potential treatments for neurodegenerative diseases like ALS. The model is specifically for Alexander disease (AxD) because of its relatively simple pathology. But it’s relevant to Alzheimer’s, Parkinson’s, and ALS because it focuses in on malfunctioning astrocytes. In AxD, astrocytes with a mutation in glial fibrillary acidic protein (GFAP) secrete a protein called CHI3L1, a marker of neuroinflammation that suppresses neural development-related processes, including myelination. The CHI3L1 suppresses cells that are precursors to oligodendrocytes, the cells that wrap the neural axons in a fatty substance called myelin. Myelin acts like the plastic insulation of electrical wires and performs much the same function. The idea is that by understanding more about astrocytes that would reveal clues about how to treat diseases like Alzheimer’s and ALS.
And that’s all for this episode of the C-to-the-Three Podcast on ericvalor.org. I am, and always will be, Eric Valor. Until next time, breathe easy.