Progenitor Cells Secreting GDNF for the Treatment of ALS

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Award Value: 
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
Public Abstract: 

This project aims to use a powerful combined neural progenitor cell and growth factor approach to treat patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease). ALS is a devastating disease for which there is no treatment or cure. Progression from early muscle twitches to complete paralysis and death usually happens within 4 years. Every 90 minutes someone is diagnosed with ALS in the USA, and every 90 minutes someone dies from ALS. In California the death rate is one person every one and a half days. Human neural progenitor cells found early in brain development can be isolated and expanded in culture to large banks of billions of cell. When transplanted into animal models of ALS they have been shown to mature into support cells for dying motor neurons called astrocytes. In other studies, growth factors such as glial cell line-derived growth factor (or GDNF) have been shown to protect motor neurons from damage in a number of different animal models including ALS. However, delivering GDNF to the spinal cord has been almost impossible as it does not cross from the blood to the tissue of the spinal cord. The idea behind the current proposal is to modify human neural progenitor cells to produce GDNF and then transplant these cells into patients. There they act as “Trojan horses”, arriving at sick motor neurons and delivering the drug exactly where it is needed. A number of advances in human neural progenitor cell biology along with new surgical approaches have allowed us to create this disease team approach.
The focus of the proposal will be to perform essential preclinical studies in relevant preclinical animal models that will establish optimal doses and safe procedures for translating this progenitor cell and growth factor therapy into human patients. The Phase 1/2a clinical study will inject the cells into one side of the lumbar spinal cord (that supplies the legs with neural impulses) of 12 ALS patients from the state of California. The progression in the treated leg vs. the non treated leg will be compared to see if the cells slow down progression of the disease. This is the first time a combined progenitor cell and growth factor treatment has been explored for patients with ALS.

Statement of Benefit to California: 

ALS is a devastating disease, and also puts a large burden on state resources through the need of full time care givers and hospital equipment. It is estimated that the cost of caring for an ALS patient in the late stage of disease while on a respiration is $200,000-300,000 per year. While primarily a humanitarian effort to avoid suffering, this project will also ease the cost of caring for ALS patients in California if ultimately successful. As the first trial in the world to combine progenitor cell and gene transfer of a growth factor, it will make California a center of excellence for these types of studies. This in turn will attract scientists, clinicians, and companies interested in this area of medicine to the state of California thus increasing state revenue and state prestige in the rapidly growing field of Regenerative Medicine.

Progress Report: 

ALS is a devastating disease for which there is no treatment or cure. Death of motor neurons in the spinal cord responsible for muscle function, results in complete paralysis and death usually within 2-4 years following diagnosis. This project will transplant stem cells secreting the powerful growth factor GDNF into the spinal cord of patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease) do delay motor neuron death and thus treat the disease. In the first year we have (i) put together an outstanding team that have been able to begin the process of all pre clinical studies required to reach a new investigational drug (IND) filing within two years, (ii) generated a bank of research grade neural stem cells producing GDNF and developed manufacturing protocols at clinical grad level to produce the final lot of cells for the trial, (iii) performed complete dose ranging studies in a rat model of ALS to generate the first set of data showing safety and optimal doses for the cell product, (iv) optimized parameters to perform small and large animal safety studies required to take this work to the clinic and (v) assembled an outstanding team of clinicians and developed a world leading ALS clinic that is now preparing for patients to enter this trial. In the next year, we hope to complete the clinical grade lot of stem cells producing GDNF, to complete the remaining safety studies in rodent and pigs that will allow us to submit the IND application enabling a Phase 1/2a clinical study in 18 ALS patients from the state of California.

The goal of this project is to produce a clinical grade of human neural progenitor cells that are modified to release the powerful growth factor GDNF that protects dying motor neurons in the spinal cord. In year 2 of this project, we have significantly advanced all aspects of the study and overcome a major hurdle related to the production of the clinical grade human neural progenitor cells (our product that is called CNS10-NPC-GDNF). The challenge was to scale up our laboratory methods (where we produce only a few vials of the cells for lab use) to a clinical grade set of over 1000 vials. Thanks to a major collaborative effort with the City of Hope, many weeks of trouble shooting, and the tenacity of our own scientists, and the CIRM funding, we are happy to report that we now have a clinical grade lot of cells (1,200 vials) for use in all of our animal testing studies and the clinical trial itself. In addition we have now completed all of our dose ranging studies and demonstrated that transplantation CNS10-NPC-GDNF in the lumbar spinal cord of an ALS rat model has a neuroprotective effect on motor neurons at all doses investigated. During this year we have completed more pilot studies in the pig using a novel delivery device (developed by Cedars-Sinai) that will now be used to deliver the cells to the spinal cord of the patients in the trial and is currently moving though the regulatory pathway. Our ALS clinic has expanded rapidly over the past year and implemented more extensive patient testing using the new CIRM funded ATLAS chair to assess overall body strength. Given the size of our clinic we are now confident of recruiting enough patients within southern California to alter the trial from multi sites to a single site within California – Cedars-Sinai. This will allow a more focused approach and development of this novel treatment locally – with subsequent expansion to more sites. We have recruited more members of the clinical team to allow for this. Finally we have continued to present our results at meetings around the world and publish our data in the spirit of communicating this important work to both the scientific community and public.

This has been a very exciting year for this project. We have grown our ALS clinic to over 200 patients in preparation for our uni-site combined stem cell and growth factor trial. At the same time we have completed a large range of studies that have enabled a 4,500 page IND application to be prepared and submitted to the FDA on March 16th 2016. . This includes sections on cell production, animal studies supporting the trial, production of a clinical protocol that will drive the trial and all of the regulatory components necessary to allow us to move forward at Cedars-Sinai. FDA will have a month to respond to our request for the clinical program to start. Providing we achieve FDA approval, we look forward to moving into patients with ALS thanks to the continual support of this CIRM disease team award.