Jan Nolta Lab: Huntington's disease Research at The University of California Davis - 2016

Our HD  research on mesenchymal stem cells engineered to produce Brain-Derived Neurotrophic Factor is going well and we are working hard daily toward future clinical trials. Our PRE-CELL clinical trial is wrapping up at the University of California Davis Huntington's disease Center of Excellence.

We originally had CIRM funding but that ended after two years of lab work. FDA has requested some additional studies. We are currently re-applying to CIRM and raising funds to move the pipeline forward. 

Please see our recent 2015-2016 HD and JHD research publications:

Neural Regeneration Research. 2016 May;11(5):702-5. doi: 10.4103/1673-5374.182682.

Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells. http://www.ncbi.nlm.nih.gov/pubmed/27335539.

Expert Opin Biological Therapy. 2016 May 21:1-9. [Epub ahead of print]

Engineered BDNF producing cells as a potential treatment for neurologic disease. http://www.ncbi.nlm.nih.gov/pubmed/27159050.



Molecular Therapy (Nature Publishing Group). 2016 May;24(5):965-77. doi: 10.1038/mt.2016.12. Epub 2016 Jan 14.

Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models. http://www.ncbi.nlm.nih.gov/pubmed/26765769.



Regenerative Medicine. 2015;10(5):623-46. doi: 10.2217/rme.15.25.

Developing stem cell therapies for juvenile and adult-onset Huntington's disease. http://www.ncbi.nlm.nih.gov/pubmed/26237705.

Cell Transplant. 2016;25(4):677-86. doi: 10.3727/096368916X690863. Epub 2016 Feb 4. Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington's Disease Fibroblasts. http://www.ncbi.nlm.nih.gov/pubmed/26850319



Transfusion. 2016 Apr;56(4):15S-7S. doi: 10.1111/trf.13564. "Next-generation" mesenchymal stem or stromal cells for the in vivo delivery of bioactive factors: progressing toward the clinic. http://www.ncbi.nlm.nih.gov/pubmed/27079315. 

 

HD update (please see the next page for JHD update)

MSC/BDNF studies: We have completed our CIRM-funded studies using the human MSC product in immuen suppressed HD Mice and have published the manuscript reporting the successful research in press in the prestigious journal "Molecular Therapy" (listed above).

CIRM funding for the PRE-CELL trial has just ended. We will apply once again to CIRM and ohter sources to accomplish the additional short-term studies requested by the FDA. Fingers crossed. Research is unfortunately stalled due to lack of funding.

We also seek an industry partner to help take the MSC/BDNF platform forward.

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Archives:

Dr. Nolta interview:

 Ivanhoe interview- Dr. Jan Nolta

The lead-in clinical trial, Pre-Cell, is enrolling patients at UC Davis. Please see ClinicalTrials.gov study identifier NCT01937923 and the notice attached below for information.

Pre-Cell Flyer

With the outstanding leaders of our UC Davis Movement Disorders Clinic/Center of Excellence, Dr. Vicki Wheelock and Terry Tempkin, we were awarded a Disease Team Grant from the California Institute for Regenerative Medicine (CIRM). This grant funded our IND-enabling studies working toward a planned future clinical trial to use mesenchymal stem cells to deliver Brain-Derived Neurotrophic Factor (BDNF) to potentially rescue striatal neurons in HD patients. BDNF plummets to very low levels in HD, due to interference from the mutant protein, and it is needed to keep neurons alive and maintaining communication with one another in the striatum. 

Through generous donations from TeamKJ, Les and Margaret Pue, the Roberson foundation, and other dedicated patient advocates, we have shown that mesenchymal stem cells from a healthy and qualified donor can be engineered to produce high levels of BDNF, and that infusion into the brain of rodents with HD and large animals is safe. We thank our donors, without whom this work could never have been possible.

Our excellent collaborator, Dr. Gary Dunbar at the Central University of Michigan, has shown that MSCs engineered to produce BDNF restore normal function and movement in HD rodents for at least one year:

Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington's disease.

Dey ND, Bombard MC, Roland BP, Davidson S, Lu M, Rossignol J, Sandstrom MI, Skeel RL, Lescaudron L, Dunbar GL.

PMID: 20493905 [PubMed - indexed for MEDLINE]

HDSA report on this technology:

http://www.hdsa.org/images/content/1/3/13054.pdf

We have published an article describing our MSC/BDNF technology with Gary Dunbar:

Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease.

Olson SD, Pollock K, Kambal A, Cary W, Mitchell GM, Tempkin J, Stewart H, McGee J, Bauer G, Kim HS, Tempkin T, Wheelock V, Annett G, Dunbar G, Nolta JA.

PMID:22161544 [PubMed - in process] Free PMC Article

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Link to the HD page about our research in the California Institute for Regenerative Medicine's Annual Report:

http://cirm.ca.gov/2010AnnualReport_HD

HD archives:

From 2012: Great news!!!! the UC Davis HD team has received funding to move toward the proposed Phase I clinical trial of MSC/BDNF, and to complete the trial once all regulatory approvals are obtained!

For pictures from the day of the ICOC vote and celebration please click here

http://www.ucdmc.ucdavis.edu/publish/news/newsroom/6808/?mode=draft

http://www.thehuntingtonspost.org/

http://www.curehd.blogspot.com/

CBS news:

http://sanfrancisco.cbslocal.com/2012/07/27/california-stem-cell-agency-approves-150m-in-grants-to-fight-diseases/

San Francisco Chronicle Article

For our disease team celebration party photos

please click here!



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Through the Planning Grant from CIRM (Wheelock/Nolta DR2A-05415), we have designed and propose a novel therapy to treat HD. The approach is implantation of mesenchymal stem cells engineered to secrete Brain-Derived Neurotrophic Factor (BDNF), a factor needed by neurons to remain alive and healthy. BDNF plummets to very low levels in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease.

Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects and is safe in animal models. MSC are ideally suited for cellular therapy due to their ease of isolation, manipulation, and safety. They can be expanded from normal qualified human donors in large quantities and can be infused without tissue matching, since they shield themselves from the immune system. The ability to be transplanted without tissue matching has allowed large multi-center trials to be conducted with direct comparison of the same batches of MSC across thousands of patients, without adverse events or rejection reactions:

Companies such as Osiris, Mesoblast, Aastrom and Athersys  are in Phase I – III clinical trials using large lots of MSCs, or MSC-like cells, expanded from a single or several donors.

The cells are infused without tissue matching, due to their ability to shelter themselves from the immune system.

San-Bio is currently testing a gene-modified MSC therapeutic  by delivery into the brain in Phase I clinical trials to treat stroke:

http://clinicaltrials.gov/ct2/show/NCT01287936?term=sb623&rank=1

The latter trial provides an excellent precedent for our planned approach.

We have discovered that MSC are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with enhanced neurotrophic factor secretion to enhance the health of at-risk neurons. Working with national and international collaborators, our novel animal models are allowing the proposed therapy to be carefully tested in preparation for a phase I clinical trial of MSC/BDNF infusion into the brain tissue of HD patients, with the goal of restoring the health of neurons that have been damaged by the mutant htt protein.

Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further work to ensure that the proposed therapy will be safe and effective, in preparation for the phase I clinical trial. The significance of our studies is very high because there are currently no treatments to diminish the unrelenting decline in the numbers of medium spiny neurons in the striata of patients affected by HD. Our biological delivery system for BDNF could also be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where neuroregeneration is needed. Development of novel stem cell therapies is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families.

Our plans for development of this therapy, and for furthering our RNAi research, are 100% reliant on obtaining funding. Please wish us luck!