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)
JHF currently funds two 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. Zarnescu 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.
This past year, the Zarnescu group made significant progress in the area of ALS research. The laboratory continued to primarily use the fruit fly as a simple, rapid and cost effective model to study the molecular mechanisms underlying ALS and to develop therapeutic strategies for motor neuron and related neurodegenerative diseases. In addition, Dr. Zarnescu established several successful collaborations with colleagues across the US to validate discoveries from the fruit fly in mouse models, patient derived iPS cells and patient tissues. She secured new funding, published several articles and additional manuscripts are in preparation. Key highlights include the discovery of a novel mechanism for synaptic failure across several types of ALS (familial and sporadic) and the identification of specific defects in cellular metabolism that pinpoint specific dietary interventions to protect motor neurons from dying. In addition, Dr. Zarnescu’s group identified several novel drug-like molecules that rescue ALS defects in the fruit fly model and are ready to be tested in patient derived cells.
Research Dr Madhavan’s laboratory broadly centers on Stem Cells and Neurological Disorders, with the ultimate goal of developing effective treatments for conditions such as Parkinson's disease and Amytrophic Lateral Sclerosis (ALS). In this context, the lab has recently taken advantage of a modern stem cell technology, called induced pluripotent stem cell technology. Induced pluripotent stem cells, or iPS cells, are generated through a method called 'reprogramming' via which adult cells, such as skin cells, are converted into pluripotent or embryonic-like cells. These embryonic-like iPS cells can subsequently be turned into any other cell-type of the human body. With respect to ALS, iPS cells represent a unique resource for generating specific neuronal cells like motor neurons which degenerate in this disorder, and which can otherwise not be obtained directly from living individuals afflicted with the disease. Using such iPS-derived neuronal cells, the lab plans to study the mechanisms underlying ALS - particularly since these cells can act as authentic 'reporters' of what might be altered or going wrong in the tissues of affected individuals. Additionally, these iPS-derived neuronal cells can also be used as a platform to test novel drugs for ALS. The lab has already created iPS cells from individuals diagnosed with Parkinson's disease, and they are currently extending this technology to ALS. A future aim is to generate clinical-grade iPS-derived neural cells, relevant to Parkinson's disease and ALS, which can be implanted into patients to replace or repair degenerating cells thus acting as effective therapeutic to slow or stop the progression of these diseases.
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.
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 firstname.lastname@example.org
To Learn More about ALS please refer to the following links:
Research paper by the U of A Department of Neurology (PDF document)