Status:Suspended
Keywords:iPSC
, stem cells
, Ataxia
, SCA
, Parkinson's disease
, PD
IRB Number:00035794
Specialty:
Sub Specialty:
Spinocerebellar ataxia (SCA) is a group of genetic disorders characterized by slow progressive incoordination of gait due to failure of fine coordination of muscle movements often associated with poor coordination of hands, speech and eye movements. The symptoms of ataxia vary with the specific type and with the individual patient. Persons with spinocerebellar ataxia experience degeneration of the spinal cord and the cerebellum.
Parkinson's disease (PD) is one of a larger group of neurological conditions called motor system disorders. There is no one particular test that can be done to diagnose Parkinson's disease. Diagnostic techniques range from genetic testing, testing of the olfactory and autonomic system, neurophysiological testing and neuroimaging. Currently there is no cure or long term treatment for Parkinson’s disease. Parkinson's disease is even more difficult to diagnose in the early stages, when there are less symptoms. Symptoms include trembling, trouble with writing, and changes in gait.
In several of the SCAs the disease causing mutation is the expansion of a polymorphic CAG trinucleotide repeat. The clinical hallmark of this mutation is anticipation, the earlier onset of disease often accompanied by more severe symptoms in succeeding generations of affected families. In this way, it is similar to fragile X syndrome, Huntington disease and myotonic dystrophy. At this time there are 29 different SCAs, plus 4 X-linked types that have been described for which only 1 gene has been found.
There is no known cure for spinocerebellar ataxia and Parkinson’s disease, treatments are generally limited to softening symptoms but the conditions are irreversible.
Many patients with hereditary or idiopathic forms of ataxia and Parkinson’s disease have other symptoms in addition to ataxia and tremors. Our group has leaded the home front in neurodegenerative disease research with over two decades of experience in the field and at least 139 publications. Research in our laboratory focuses on inherited diseases of the nervous system with an emphasis on spinocerebellar ataxias and movement disorders. Our group identified genes for Spinocerebellar type 2 (SCA2)[1] and Spinocerebellar type 13 (SCA13) [2, 3]and as part of collaborative groups, the genes for SCA10 [4]and Neurofibromatosis 2.
Lorenzo Nanetti et al describes a rare association of motor neuron disease (MND) and spinocerebellar ataxia type 2 (SCA2) [5] where the patient several years the onset of the cerebellar symptoms, developed a rapidly progressive form of motor neuron disease. The patient died from acute respiratory failure within 24 months after the onset of motor neuron signs. Per literature review there have been eleven patients reported to have had concomitant SCA and MND. One patient had SCA6 mutation [6, 7], two unrelated patients had SCA2 [8, 9] and the other eight [10] remaining cases no molecular defect was identified; perhaps it is possible that a genetic diagnosis was missed when these later eight were described.
Although there is a lot of ongoing research to learn more about SCA and develop treatments, no cure currently exists for the SCAs. Most people with SCAs do have progression of their symptoms that leads to full time use of a wheelchair and eventually death.
In a society that expects at least some treatment for diseases, SCAs stand out as rare examples where little to nothing can be done. The root of the problem is that we currently do not understand what causes the variability in phenotypes and their progression. While many genes have been linked to the different SCAs they have given only clues as to the possible origins of these diseases and their functionality.
Traditionally, advancements in medicine have relied on studying post mortem organs from patients in order to understand more about what may have caused the problem and then developing animal models to test new therapies. However, for chronic and relatively rare degenerative diseases of the central nervous system such as SCAs this has proven to be a huge challenge. The current study being proposed is to test a new and exciting hypothesis based on recent advances in the field of stem cell biology. We would like to ask whether motor neurons generated from patients with SCA are different form motor neurons generated from normal controls. Until very recently, it would not be possible to address this question.
However at the end of 2007 a milestone was achieved by creating iPS from adult human cells, these results were reported by two independent research teams one lead by Dr. J. Thomson and Dr. J. Yu at the University of Wisconsin and the other by Dr. Shinya Yamanaka at Kyoto University in Japan. The Yamanaka team used the same principle used in mouse models transforming human fibroblast into pluripotent stem cells using the pivotal genes Oct3/4, Sox2, Klf4 and c-Myc with a retroviral system [11]. Dr. J Thomson and Dr. Yu’s team utilized Oct4, Sox2, Nanog and a different gene LIN28 using a lentiviral system[12]. And although more recently a group under the leadership of Dr. Sheng Ding in La Jolla, California could show that the generation of iPS cells was possible without any genetic alteration in the adult cell, his work is in the generation of protein-induced pluripotent stem cells (piPSCs) from murine embryonic fibroblasts using recombinant cell-penetrating reprogramming proteins[13]. This procedure might eventually lead to therapeutic use since this creation of iPS cells does not involve viruses.
Once iPS cells have been generated, they can be expanded indefinitely and then transformed into any tissue of the body including motor neurons and purkinje cells. Our collaborator Dr. Clive Svendsen PhD at the University of Wisconsin has now shown that iPS cells can be generated from banks of commercially available skin cells from patients with another neurological disease involving loss of motor neurons called spinal muscular atrophy (SMA) [14]. These SMA-iPS cells can make neurons in the culture dish and show some of the same problems that they exhibit in patients. We now propose to do the same with SCA and Parkinson’s disease, however there are no banks of commercially available skin cells for us to use.
Recent studies have shown the therapeutic application for the transplantation of iPS derived dopamine neurons (brain cells) in a rat model of Parkinson’s disease. In these studies it was shown that dopamine neurons could be functionally integrated into the adult rat model of Parkinson’s disease, and that this could lead to an improvement in the clinical symptoms of the disease. Similar experiments were also performed on hemophilia A mice (iPS derived endothelial cells into liver cells) and this also resulted in disease improvement (hemophilia is a blood disease). Hence, iPS cell-based strategies could become very important in the future treatment of Spinocerebellar Ataxias and Parkinson’s disease.
Spinocerebellar ataxia (SCA) is a group of genetic disorders characterized by slow progressive incoordination of gait due to failure of fine coordination of muscle movements often associated with poor coordination of hands, speech and eye movements. The symptoms of ataxia vary with the specific type and with the individual patient. Persons with spinocerebellar ataxia experience degeneration of the spinal cord and the cerebellum. Parkinson's disease (PD) is one of a larger group of neurological conditions called motor system disorders. There is no one particular test that can be done to diagnose Parkinson's disease. Diagnostic techniques range from genetic testing, testing of the olfactory and autonomic system, neurophysiological testing and neuroimaging. Currently there is no cure or long term treatment for Parkinson’s disease. Parkinson's disease is even more difficult to diagnose in the early stages, when there are less symptoms. Symptoms include trembling, trouble with writing, and changes in gait. In several of the SCAs the disease causing mutation is the expansion of a polymorphic CAG trinucleotide repeat. The clinical hallmark of this mutation is anticipation, the earlier onset of disease often accompanied by more severe symptoms in succeeding generations of affected families. In this way, it is similar to fragile X syndrome, Huntington disease and myotonic dystrophy. At this time there are 29 different SCAs, plus 4 X-linked types that have been described for which only 1 gene has been found. There is no known cure for spinocerebellar ataxia and Parkinson’s disease, treatments are generally limited to softening symptoms but the conditions are irreversible. Many patients with hereditary or idiopathic forms of ataxia and Parkinson’s disease have other symptoms in addition to ataxia and tremors. Our group has leaded the home front in neurodegenerative disease research with over two decades of experience in the field and at least 139 publications. Research in our laboratory focuses on inherited diseases of the nervous system with an emphasis on spinocerebellar ataxias and movement disorders. Our group identified genes for Spinocerebellar type 2 (SCA2)[1] and Spinocerebellar type 13 (SCA13) [2, 3]and as part of collaborative groups, the genes for SCA10 [4]and Neurofibromatosis 2. Lorenzo Nanetti et al describes a rare association of motor neuron disease (MND) and spinocerebellar ataxia type 2 (SCA2) [5] where the patient several years the onset of the cerebellar symptoms, developed a rapidly progressive form of motor neuron disease. The patient died from acute respiratory failure within 24 months after the onset of motor neuron signs. Per literature review there have been eleven patients reported to have had concomitant SCA and MND. One patient had SCA6 mutation [6, 7], two unrelated patients had SCA2 [8, 9] and the other eight [10] remaining cases no molecular defect was identified; perhaps it is possible that a genetic diagnosis was missed when these later eight were described. Although there is a lot of ongoing research to learn more about SCA and develop treatments, no cure currently exists for the SCAs. Most people with SCAs do have progression of their symptoms that leads to full time use of a wheelchair and eventually death. In a society that expects at least some treatment for diseases, SCAs stand out as rare examples where little to nothing can be done. The root of the problem is that we currently do not understand what causes the variability in phenotypes and their progression. While many genes have been linked to the different SCAs they have given only clues as to the possible origins of these diseases and their functionality. Traditionally, advancements in medicine have relied on studying post mortem organs from patients in order to understand more about what may have caused the problem and then developing animal models to test new therapies. However, for chronic and relatively rare degenerative diseases of the central nervous system such as SCAs this has proven to be a huge challenge. The current study being proposed is to test a new and exciting hypothesis based on recent advances in the field of stem cell biology. We would like to ask whether motor neurons generated from patients with SCA are different form motor neurons generated from normal controls. Until very recently, it would not be possible to address this question. However at the end of 2007 a milestone was achieved by creating iPS from adult human cells, these results were reported by two independent research teams one lead by Dr. J. Thomson and Dr. J. Yu at the University of Wisconsin and the other by Dr. Shinya Yamanaka at Kyoto University in Japan. The Yamanaka team used the same principle used in mouse models transforming human fibroblast into pluripotent stem cells using the pivotal genes Oct3/4, Sox2, Klf4 and c-Myc with a retroviral system [11]. Dr. J Thomson and Dr. Yu’s team utilized Oct4, Sox2, Nanog and a different gene LIN28 using a lentiviral system[12]. And although more recently a group under the leadership of Dr. Sheng Ding in La Jolla, California could show that the generation of iPS cells was possible without any genetic alteration in the adult cell, his work is in the generation of protein-induced pluripotent stem cells (piPSCs) from murine embryonic fibroblasts using recombinant cell-penetrating reprogramming proteins[13]. This procedure might eventually lead to therapeutic use since this creation of iPS cells does not involve viruses. Once iPS cells have been generated, they can be expanded indefinitely and then transformed into any tissue of the body including motor neurons and purkinje cells. Our collaborator Dr. Clive Svendsen PhD at the University of Wisconsin has now shown that iPS cells can be generated from banks of commercially available skin cells from patients with another neurological disease involving loss of motor neurons called spinal muscular atrophy (SMA) [14]. These SMA-iPS cells can make neurons in the culture dish and show some of the same problems that they exhibit in patients. We now propose to do the same with SCA and Parkinson’s disease; however there are no banks of commercially available skin cells for us to use and frozen blood or immortalized lymphoblast cells are not compatible with current techniques. Recent studies have shown the therapeutic application for the transplantation of iPS derived dopamine neurons (brain cells) in a rat model of Parkinson’s disease. In these studies it was shown that dopamine neurons could be functionally integrated into the adult rat model of Parkinson’s disease, and that this could lead to an improvement in the clinical symptoms of the disease. Similar experiments were also performed on hemophilia A mice (iPS derived endothelial cells into liver cells) and this also resulted in disease improvement (hemophilia is a blood disease). Hence, iPS cell-based strategies could become very important in the future treatment of Spinocerebellar Ataxias and Parkinson’s disease.
Principle Investigator: Stefan Pulst
Principle Department: Neurology
Co Investigator:
Name:Karla Figueroa
Phone:801-585-1077
Email:karla.figueroa@genetics.utah.edu
Our subject population will be SCA and PD patients and their unaffected family member or normal controls between the age of 18 and 70. Both female and male patients and controls will be sampled. Unaffected family member or normal controls will serve as an important control group for this study, genetically related but without SCA or PD
If participant is suseptible to keloids he/she might be excluded for the comfort and safety of the patient.
