fundraising $1,000,000 in seed money to eradicate ALS
The Jim Himelic Neuromuscular Research Laboratory
The Jim Himelic Foundation funds ALS research in the laboratory and clinical setting at the University of Arizona’s College of Medicine Department of Neurology. The UA’s neuromuscular research program is part of the Western ALS Study Group, a consortium of dedicated ALS investigators from around the nation, and the Neurogenomics Division of the Translational Genomics Research Institute (TGen) in Phoenix, a leader in the field of genomic discovery.
In May 2004, the UA Department of Neurology’s stem cell laboratory officially was named “The Jim Himelic Neuromuscular Research Laboratory” (Video of dedication). Dr. Bruce Coull, Dr. Timothy Miller, and Dr. Jonathan Flax dedicated the laboratory to the Himelic family in return for all the funding received through the Himelic Fund.
At the Jim Himelic Neuromuscular Research Laboratory, researchers are developing novel techniques to activate cells called progenitors – found in the brain and spinal cord of adults – to form new nerve cells. During human development from the embryonic (first eight weeks) through the fetal (eight weeks to birth) periods, these progenitors produce almost all of the nerve cells in the brain and spinal cord. Once this task is complete, progenitors generate other brain cells but do not make new nerve cells.
The goal of UA researchers is to “re-train” these progenitors – which remain present in the adult brain and spinal cord – to produce new nerve cells. In this manner, researchers hope to replace the nerve cells that have died in ALS patients with new functional nerve cells, potentially slowing or possibly even reversing the course of the disease. If successful, this approach may also be used to replace other types of nerve cells that are lost in other neurologic diseases such as Parkinson’s and Alzheimer’s.
The Himelic Fund for ALS Research Brochure (pdf file)
KUAT/PBS story on ALS research at the U of A
Status of ALS Research in Other Laboratories
Learn More About ALS (new research update from U of A)
JHF ALS Researchers
JHF currently funds three researchers at the Jim Himelic Neuromuscular Research Laboratory at the UA College of Medicine Department of Neurology. Below is an outline of the work currently being conducted by each researcher.
Dr. Scherer:
Neurologists Katalin Scherer, MD and Holli Horak, MD from the Neuromuscular Program and Clinics at the University of Arizona Department of Neurology are applying ALS research in a clinical setting at the MDA/ALS Center at UPH Hospital. This ALS multidisciplinary clinic opened in August 2008 at University Physicians Hospital and Clinics and is located at 2800 E. Ajo Way in Tucson, AZ. The center is one of only 37 facilities at major medical institutions in the country designated by the Muscular Dystrophy Association as MDA/ALS Centers, indicating the high level or expert medical care and clinical research taking place there. With the help of the ALS clinic established by Dr. Scherer, JHF hopes to fund local and national multi-center clinical trials based on the ALS patient base of Southern Arizona. For more information about the MDA/ALS Center at UPH Hospital, please call the clinic’s administration line at (520) 874-2747 or visit their website.
Dr. Zarnescu:
Daniela C. Zarnescu, PhD, is a UA assistant professor of molecular and cellular biology and neurobiology who is partially funded by JHF and is working in the Jim Himelic Neuromuscular Research Laboratory. Dr. Zarnescu is using the fruitfly (Drosophila) model to study the effects of ALS. Because there is a high degree of similarity between Drosophila and human disease genes, the fruitfly is a powerful genetic system to study basic aspects of human neurological and neurodegenerative disorders. Already, a number of genes have been linked to cases of familial ALS, which makes up about 10% of all cases, yet the majority of ALS cases (sporadic ALS) is due to mutations in several genes, most of which remain to be discovered. Dr. Zarnescu says, “A gene called TDP-43 has emerged as a common denominator for the majority of ALS cases known to date, both inherited and sporadic. We are well on our way to establish a Drosophila model for ALS based on TDP-43.” Dr. Zarnescu believes her research will uncover therapeutic agents that will target the abnormal TDP-43 cell material aggregates, which produce malfunctioning proteins in the cells that result in the buildup of cytoplasm. Abnormal TDP-43 cells are a hallmark of ALS and other human neurodegenerative disorders. “We may discover approaches that are applicable to diseases other than ALS such as Alzheimer’s and Fronto-Temporal Lobar Dementia” she says. Dr. Zarnescu’s work is also well positioned to discover novel genes involved in ALS.
Dr. Estevez:
Dr. Miguel Estevez MD, PhD is studying the impact of calcium levels in nervous system cells to determine the probability of cell survival. Motor neurons from ALS patients show abnormally elevated calcium levels, which is important because calcium in any cell in the nervous system beyond a critical level will trigger cell death. Therefore, Dr. Estevez hypothesized and confirmed that a mouse strain with elevated calcium levels in its cells is likely to develop loss of its motor neurons, similar to what is seen in ALS patients. Thus, by comparing the spinal cord of populations of the control adult mice with that in populations of the test adult mice, Dr. Estevez has found that only the latter mice developed motor neuron loss in early adulthood. Dr. Estevez intends to use these findings to help identify candidate medicines effective in a broader spectrum of ALS cases based on their ability to suppress motor neuron death in the test mouse strain. Dr. Estevez’s goal is to bring at least one candidate ALS drug to a Phase 1 trial, which is the first stage of drug testing on human subjects, within in the next five years.
Dr. Flax:
Note: Although Dr. Flax is no longer at the University of Arizona Department of Neurology, he is continuing his research at Cornell University. In addition, the University of Arizona will continue to be cited as a contributor for any future results related to Dr. Flax’s work, which is outlined below.
Dr. Flax’s long-term goal is to acquire the ability to force neural stem cells (NSCs) to alter into motor neurons and replace those lost in ALS patients. Dr. Flax’s laboratory research is focused on two objectives:
- To understand and overcome the intrinsic blocking of adult spinal cord NSCs that prevents them from undergoing motor neuron differentiation.
- The complete characterization of the functions of two identified packaging proteins responsible, in part, for this blocking within the next year.
Currently, Dr. Flax is focusing on how late spinal NSCs switch from the immature state to the mature state. Other labs have found that there is an intrinsic blocking mechanism in late spinal NSCs that prevent them from being directed by foreign signals. In the last 3 years, Dr. Flax has found that NSCs in older animals also have an active block to becoming motor neurons. This block appears to be, in part, due to a change in the physical structure of the genes that direct NSCs to differentiate into neuronal cells. The change stems from the way in which the genes are packaged by its surrounding proteins.
This packaging encases the genes in a protein coat and wraps them in a tight bundle such that they can’t be effectively turned on. If the genes can’t be turned on, the NSCs can’t be turned into new motor neurons. Fortunately, this gene packaging is potentially reversible. If the packaging can be removed, the genes can be turned on and adult NSCs can produce new motor neurons. Identifying the key molecular players that mediate this gene packaging (gene silencing) is the required first step.
Two proteins that play a key role in this process have been successfully identified. The first packaging protein operates early in embryonic development and appears to regulate NSC differentiation by silencing genes that direct alternative choices (i.e., by closing off alternative fate choices, the available options for an NSC become limited). The second protein is involved in orchestrating the formation of neural circuits (including motor neurons) during development. Initial findings at the lab suggest that this second packaging protein may silence alternative choices of circuits. Because motor neurons are required to make correct connections with both muscle and other neurons, understanding and reactivating the genes that establish the circuitry within the motor neuron may be critical for adult NSC-derived motor neurons to become functional. Molecular tools have been developed to modulate the activity of these packaging proteins and testing will be done to see if elimination of these packaging proteins will allow for NSCs to being forming motor neurons. If initial approaches are successful, clinical partners will be established to push forward with human clinical trials.
Status of ALS Research in Other Laboratories
Neurologists in other research laboratories are currently focusing on identifying the genes which cause familial ALS (FALS), responsible for approximately 10% of all cases, and understanding how these mutant genes cause the disease and how this pathologic process may be related to spontaneous ALS (SALS). Scientists have identified four genes responsible for or which predispose individuals the FALS. In addition to these identified genes, there are a number of genetic loci that harbor yet to be discovered FALS-causing genes. Given that many of the features of FALS and SALS are similar, discovering how these mutations cause FALS may shed light on how SALS occurs. However, the majority of SALS cases don't appear to be due to these known mutations.
Exciting research from other laboratories focuses on differentiating embryonic stem cells (cell lines derived from fertilized mouse and human eggs) into motor neurons, and transplanting these cells into animal models of ALS. Recent work from the Rothstein and Kerr Laboratories have demonstrated that embryonic stem cells in a culture dish that have been ordered to differentiate into a motor neuron fate then subsequently transplanted into the spinal cord of rats, which have previously had their motor neurons destroyed by a virus, are able to mature and survive in the spinal cord. In addition, when chemicals that allow axons to grow in the adult spinal cord are used in combination with NSCs an attractant for the motor neuron axons is produced. Placed in the peripheral nerve roots, these embryonic stem cell-derived motor neurons make functional connections with the muscle, partially reversing paralysis.
In addition to research on FALS, developing targeted therapeutic approaches to these disease processes and testing them in both animal and human trials continues to make progress. The Koliatsos Laboratory has transplanted human NSCs into the spinal cords of ALS mice, and their researchers have demonstrated that the engrafted cells differentiated into neurons. Their research also has shown that those animals with engrafted cells showed later onset and a slower progression of the motor neuron disease and lived longer compared with control animals. Thus, transplanted NSCs also have demonstrated therapeutic efficacy. This supports the idea that the differentiation of endogenous NSCs into neurons may offer significant therapeutic benefits.
How You Can Help
With this cutting edge research, scientists hope that the eradication of ALS will be a possible and hopefully even a probable goal that can be attained within most of our lifetimes. A neuromuscular research facility with a primary focus on Amyotrophic Lateral Sclerosis capable of holding stem cell experiments requires highly specialized and expensive equipment and supplies.
With your financial assistance making the creation of such a facility possible, the University of Arizona will become a forerunner in the research to help fight and cure ALS. For questions or comments regarding the laboratory, please contact the Jim Himelic Foundation at info@jimhimelicfoundation.org
Learn More About ALS
To Learn More about ALS please refer to the following links:
Muscular Dystrophy Association ALS info
New research update from U of A
Duke's Richard Bedlack, MD, PhD, "ALS-Recent Advances" Presentation Given at the U of A
Research paper by the U of A Department of Neurology (PDF document)
