Tarheel Health Portal/Induced Pluripotent Stem Cells in Huntington's Disease

From Wikiversity
Jump to navigation Jump to search

Huntington’s Disease (HD) is an autosomal dominant progressive neurodegenerative disorder in which the major gene expression occurs in the central nervous system. The disease clinically manifests as motor dysfunction, typified by involuntary movements, cognitive abnormalities and psychiatric disturbances. The genetic defect for this autosomal dominant disorder involves a DNA segment known as a CAG trinucleotide repeat expansion. This segment is made up of a series of three DNA building blocks of cytosine, adenine, and guanine that appear multiple times in a row. This trinucleotide is also a codon that is repeated many times in the coding region for the protein glutamate. This mutation takes place on the first exon of the huntingtin (HTT) gene. The HTT gene provides instruction for making the protein huntingtin that plays an important role in the neurons of the brain, although the function of this protein is unknown.[1] In people with Huntington’s Disease, the CAG segment is repeated 36 to more than 120 times in adults. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington’s Disease, while people with 40 or more repeats almost always develop the disorder. In Juvenile onset, there is an inverse correlation with CAG repeat length and onset of disease, with longer repeats, usually greater than 55 CAG repeats, associate more commonly with this onset. An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington's Disease.[2] Although this disease only wreaks havoc on 15,000 Americans, there is still a small proportion of individuals within the UNC community that are effected by Huntington's Disease, or have families who are effected by this disease. Since this disease is rarer than other neurodegenerative disorders like Parkinson's Disease, Huntington's will only act as a representative case study for the impact that induced pluripotent stem cells could potentially make for all neurodegenerative disorders that are more common to the UNC community.

Neuron with mHtt inclusion

Induced Pluripotent Stem Cells[edit | edit source]

Induced pluripotent stem cells, or iPS cells, are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state by being genetically reprogrammed and forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.[3] Embryonic stem cells are stem cells that originate from donated embryos and are grown from cells found in the embryo when it is just a few days old.[4] This type of stem cell is the most well known type of pluripotent stem cell there is in the field, but, much controversy exists pertaining to the use of them. Pluripotent stem cells are stem cells that are derived from any cell that makes up the body, but usually come from body, or somatic cells. Reprogramming is one of the main mechanisms that drive iPS cells, as it allows scientists to turn virtually any cell of the body into a pluripotent stem cell. [5]

Induced pluripotent stem cell technology was first discovered in 2006 by scientist Shinya Yamanaka, who made the first line of iPS cells by adding four genes to skin cells from a mouse. This study illustrated that within two to three weeks, the skin cells located on the mouse were converted into induced pluripotent stem cells.[5]

Pluripotent stem cells hold great potential in the field of regenerative medicine. Due to their ability to self-renew, they are able to divide and produce copies of themselves indefinitely, providing an unlimited supply of replacement cells and tissues for specific diseases.[5] In contrast to embryonic stem cells, iPS cells are derived directly from adult cells, overall bypassing the need of embryos. These stem cells are also patient and disease specific, meaning that each individual can have induced pluripotent stem cell lines that are tailored specifically to their form of the disease. This overall offers a unique chance to model rare human diseases. Cell replacement therapies are therapies that are up and coming due to the specificity of stem cell lines to the patient. This would avoid problem areas like that of immune rejection. An important step in discovering the underlying mechanism surrounding a disease is to study the cells and tissues affected by the disease. Like those who have Huntington's Disease, initially, it is almost impossible to obtain genuine brain cells from Huntington Disease patients. Reprogramming through iPS cells now allow scientists access to large numbers of brain cells from those who are stricken with Huntington's. These would be derived from a skin biopsy, where an individual's skin is grafted out and would allow iPS cells to produce neurons in the lab. This discovery, made only nine years ago, has created a powerful new way to "de-differentiate" cells from diseases whose developmental fates have been previously assumed to be determined.

Disease Modeling[edit | edit source]

Induced pluripotent stem cell technologies are becoming a key asset for deciphering pathologies and for developing new treatments against many neurodegenerative disorders, including Huntington’s Disease. The discovery of human somatic cell reprogramming to generate induced pluripotent stem cells have captured scientific interests because it can facilitate the creation of patient-specific in vitro models of specific disorders. Although promising results have been achieved with iPS cells from patients with Parkinson’s disease, late onset modifications of the disease and low availability of neuron material from the brain are often barriers to modeling due to the unknowingness of whether early pre-symptomatic changes associated with the disease are to be expected in pluripotent cells, creating questions as to whether the same could occur with those who have Huntington's Disease. The first human Huntington’s Disease iPS cell line was generated by Park and collaborators in 2008, but no data about its characteristics were presented.[6]

In a study done by Dr. Feyeux and his associate Dr. Bourgois, genuine human embryonic stem cell lines from Huntington Disease patients were researched to identify any alterations that resulted from the expression of the mutant Huntington gene (HTT) at early stages of neural development.[7] In the study, five wild type HD iPS cell lines were used as controls in the study and it was found that PGD lines in human embryonic stem cells, a version of induced pluripotent stem cells, provided a unique resource of unmodified pluripotent stem cells that carry naturally occurring HD mutations. These models identified developmental and presymptomatic phenotypes that influenced HD disease onset and progression. The PGD-derived embryonic stem cells also provided models in which the mutant gene expressed a natural genetic background of HD patients. Shortcomings are still prevalent in this area of biomedical research. IPS cells still lack the ability to maintain human neurons for long periods of time. Although late onset neurological disease might have trouble illustrating data over a wide span of time, patient specific iPS cells open up the possibility of combining animal model systems with cell transplants for studies that can look at data for a longer period of time.[8]

Neural Transplantation Using Induced Pluripotent Stem Cells[edit | edit source]

In the early 2000’s, an article written by Thomas Freeman spoke of the current progress that was made for neural transplants in brain research for Huntington’s Disease. At the time, preliminary evidence of safety, tolerability, and efficacy of fetal striatal tissues (tissue derived from nerve fibers in the brain of a human fetus) were the only factors that were even remotely successful in the transplant.[9] Since then, more researchers have examined neural transplantation in patients with HD, specifically conducting studies that look into the immunogenicity of iPS cells, or the immune response of cells that effect transplant rejection. Since iPS cells originate from the individual it is developed from, transplants should be feasible enough to use, overall avoiding an induced immune response to the transplant since they are virtually the patient's own cells.

In the year 2002, seven patients with HD underwent a bilateral transplant that involved two to eight fetal striata being implanted per side through two staged procedures.[10] After around eight to nine weeks, the tissues were dissected, and three of the subjects developed subdural hemorrages. Survival of transplanted cells was demonstrated and there was no evidence of immune rejection. Based on this study, and in the study done in 2000 by Freeman, it is apparent that HD research directed towards immunogenicity of neural grafts of iPS cells are up and coming and are making successful strides towards creating treatments that are functional enough for pre-clinical HD cell therapy . Freeman's study reported findings that proved that there was no presence of immune rejection in the microphages, or small white blood cells that assist in fighting infection, of the neural cell.[9]

Relevance to UNC Community[edit | edit source]

The University of North Carolina at Chapel Hill has a subspecialty program under the Department of Neurology that is known as The Movement Disorders Center. The UNC Movement Disorders Center is a multidisciplinary specialty group that specifically focuses on providing individualized and comprehensive care to patients who have Parkinson's Disease, and for those who have parkinsonian syndromes, like restless leg syndrome, tremors, and generalized dystonia. Movement disorders, according the movement disorders webpage at UNC are "neurological conditions that affect the speed, fluency, quality, and ease of movement."[11] Movement disorders are essentially brain cells that assist in helping individuals move, and effect those who have Tourette's syndrome and Huntington's Disease, among many others. This facility at UNC provides wonderful support for those in the community who are affected by neurological diseases that effect movement. The Movement Disorders Center also offers genetic consultations for patients with movement disorders, as well as their families.

For those who attend UNC and are care takers of a family member that has Huntington's (and any other neurological movement disorder), or has a family member that is a care taker, UNC has a number of support groups that assist in providing outlets to caretakers who are presented with challenges that effect them on mental, physical, and emotional levels.

Further Readings[edit | edit source]

As a UNC reader, here are some places you can go for more information on the topic The UNC Human Pluripotent Stem Cell Core Facility provides services to learn more about research regarding embryonic stem cells and induced pluripotent stem cells.

For support and information about Huntington's Disease, please visit the Huntington's Disease Society of America website

To get additional information about Huntington's Disease, its pathology, and genetic testing, visit NIH

To get more information from The North Carolina Center for the Care of Huntington’s Disease and read personal narratives from those who have the disease, read UNC Hospitals Huntington's Disease Brochure

A Chapel Hill native, read about Kristen Powers and her journey to increase awareness for genetic testing with those who have Huntington's Disease, see Twitch

References[edit | edit source]

Additional helpful readings include:

  1. http://www.ninds.nih.gov/disorders/huntington/detail_huntington.htm NIH (2015) Huntington's Disease: Hope Through Research
  2. http://www.ncbi.nlm.nih.gov/pubmed/ term=Astrocytes+generated+from+patient+induced+pluripotent+stem+cells+recapitulate+features+of+Huntington%E2%80%99s+disease+patient+cells Juopperi (2012) Astrocytes Generated from Patient Induced Pluripotent Stem Cells Recapitulate Features of Huntington's Disease Patient Cells
  3. http://stemcells.nih.gov/info/basics/pages/basics10.aspx NIH (2015) What Are Pluripotent Stem Cells?
  4. http://www.eurostemcell.org/factsheet/embryonic-stem-cells-where-do-they-come-and-what-can-they-do Blair (2015) Embryonic Stem Cells: Where Do They Come From and What Can They Do?
  5. 5.0 5.1 5.2 http://www.eurostemcell.org/factsheet/ips-cells-and-reprogramming-turn-any-cell-body-stem-cell Hadenfeld (2012) iPS Cells and Reprogramming: Turn Any Cell of the Body Into a Stem Cell
  6. http://www.ncbi.nlm.nih.gov/pubmed/?term=The+first+reported+generation+of+several+induced+pluripotent+stem+cell+lines+from+homozygous+and+heterozygous+Huntington%27s+disease+patients+demonstrates+mutation+related+enhanced+lysosomal+activity Camnasio et al. (2012) The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous huntington's disease patients demonstrates mutation related enhanced lysosomal activity.
  7. http://www.ncbi.nlm.nih.gov/pubmed/?term=Early+transcriptional+changes+linked+to+naturally+occurring+Huntington%27s+disease+mutations+in+neural+derivatives+of+human+embryonic+stem+cells Feyeux et al. (2012) Early transcriptional changes linked to naturally occurring Huntington's Disease Mutations in Neural Derivatives of Human Embryoninc Stem Cells.
  8. http://www.ncbi.nlm.nih.gov/pubmed/?term=Astrocytes+generated+from+patient+induced+pluripotent+stem+cells+recapitulate+features+of+Huntington%E2%80%99s+disease+patient+cells Juopperi et al. (2012) Astrocytes  Generated From Patient Induced Pluripotent Stem Cells Recapitulate Features of Huntington's Disease Patient Cells.
  9. 9.0 9.1 http://www.ncbi.nlm.nih.gov/pubmed/?term=Transplanted+fetal+striatum+in+Huntington%27s+disease%3A+phenotypic+development+and+lack+of+pathology Freeman et al (2000) Transplanted Fetal Striatum in Huntington's Disease:  Phenotypic Development and Lack of Pathology.
  10. http://www.ncbi.nlm.nih.gov/pubmed/11889229 Hauser et al (2002) Bilateral human fetal striatal transplantation in Huntington's disease.
  11. http://www.med.unc.edu/neurology/divisions/movement-disorders UNC (2015)