Jan Nolta Lab in the UC Davis Medical Center
Institute for Regenerative Cures - 2016
Brilliant people in our group, lead by talented Dr. Kyle Fink (center), working in collaboration with Dr. David Segal, Department of Genetics at UC Davis, graduate student Peter Deng and other students in our group are working on a highly exciting Gene Editing project for Juvenile Huntington's disease (JHD).
They are developing gene editing strategies using TALENs. These are molecules that go into the neural progenitor cells and actually cut out the extra CAG repeats, reducing them to the normal range of 15. So those cells should be "fixed" and go on to make neurons in the brain that are not affected by HD. This is what we need for the JHD kids- repaired neurons to be made for the rest of their- hopefully long- lives. TALES can also block expression from specific genes such as the mutant htt gene and this work is also in progress.
The team was recognized for their promising work at the 2015 meeting of the Society for Neuroscience (SFN).
The team had also presented a report at the 2014 annual meeting of the Society for Neuroscience, and a manuscript is currenlty in preparation (2016):
I am incredibly excited about this work which is designed to use the newest gene editing platform to cut out the extra CAG repeats from the patient's neural progenitors, correcting them and hopefully preventing HD from destroying them, and to silence the mutant allele.
This strategy is working in the dish and now we are poised to test it in the brains of mice with Juvenile HD.
Please stay tuned!
2014- information and progress:
Juvenile Huntington’s disease research at the UC Davis Institute for Regenerative Cures
Linked to expanded trinucleotide repeats in exon 1 of the huntingtin gene, HD causes death in 100% of those affected, through an accumulation of protein aggregates and aberrant gene regulation. The disease is characterized by striatal atrophy with clinical symptoms of chorea, cognitive decline, and psychosis. The disease is passed to half of an affected person’s children as it is a dominant gene. Currently available medications target only symptoms of the disease, are palliative, and there is no disease-modifying therapy or cure.
At the UC Davis Institute for Regenerative Cures in Sacramento we are developing cell therapies designed to slow onset and progression through intracranial injections of mesenchymal stem cells engineered to deliver brain derived neurotrophic factor (BDNF) to injured neurons. BDNF is crucial for neuron maintenance and is highly down regulated in HD patients. Research has revealed that lower BDNF levels correlate to a more severe symptomatic progression. Supplying BDNF to the brain in HD mouse models causes a slowing of symptoms and new neurons to develop in the striata. We are funded by CIRM to do this clinical trial (in adults) and have initiated the lead-in trial, Pre-Cell (ClinicalTrials.gov study identifier NCT01937923).
The form of this disease, Juvenile HD, that affects children is especially heartbreaking, rapidly progressing, and needs aggressive treatments. It is necessary to shut down expression of RNA and protein from the mutant gene, to stop its ravaging effects in the brain. At UC Davis we are continuing our published work in this area (Molecular and Cellular Neuroscience;49(3):271-81, 2012) and are working on multiple parallel strategies to accomplish the shut down:
1. Delivery of antisense DNA into striatal neurons using AAV9 vectors, which spread well through the brain. This is a collaboration with our UC Davis Tay Sachs disease program, which uses the same type of vectors.
2. Delivery of antisense DNA into striatal neurons using Mesenchymal Stem Cells (MSCs) loaded with specialized constructs. This is a collaboration with industry partners and our biotechnology program. MSCs widely distribute the constructs to damaged neurons through exosomes.
3. Gene editing to cut out CAG repeats in the mutant htt allele (Fink Lab). This is a collaboration with our UCD Department of Genetics.
We are poised to compare these strategies to determine which is most effective, using human cells and our established immune suppressed HD mouse models of behavior, movement and motor coordination.
Our PRE-CELL trial (NCT01937923 on clinicaltrials.gov) and HD CELL that will follow will, hopefully, delay progression of HD for a significant amount of time for adults but JHD is so aggressive, we need the proposed strategy of gene therapy for direct protection of the striatal neurons.
Our team is highly experienced in moving cell and gene therapy candidate products through translational IND-enabling studies to clinical trials. These studies will be accomplished and translated into a clinical trial for Juvenile HD as rapidly as possible. For JHD we know that every hour counts.
Fink et al review paper:
Stem cell therapies have been explored as a new avenue for the treatment of neurologic disease and damage within the CNS in part due to their native ability to mimic repair mechanisms in the brain. Mesenchymal stem cells have been of particular clinical interest due to their ability to release beneficial neurotrophic factors and their ability to foster a neuroprotective microenviroment. While early stem cell transplantation therapies have been fraught with technical and political concerns as well as limited clinical benefits, mesenchymal stem cell therapies have been shown to be clinically beneficial and derivable from nonembryonic, adult sources. The focus of this review will be on emerging and extant stem cell therapies for juvenile and adult-onset Huntington's disease.
Huntington's disease; regenerative medicine; stem cell; transplantation
Jan's talk at the UCSF HD symposium Feb 2012: