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Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, and indeed the disease used to be called Huntington’s chorea. It is much more common in people of Western European descent than in those of Asian or African ancestry. The disease is caused by an autosomal dominant mutation in either of an individual’s two copies of a gene called Huntingtin, which means any child of an affected parent has a 50% risk of inheriting the disease. Physical symptoms of Huntington’s disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or Westphal variant HD.
The Huntingtin gene normally provides the genetic information for a protein that is also called “Huntingtin”. The mutation of the Huntingtin gene codes for a different form of the protein, whose presence results in gradual damage to specific areas of the brain. The exact way this happens is not fully understood. Genetic testing can be performed at any stage of development, even before the onset of symptoms. This fact raises several ethical debates: at what age is an individual considered mature enough to choose testing, do parents have the right to have their children tested, and managing confidentiality and disclosure of test results. Genetic counseling has developed to inform and aid individuals considering genetic testing and has become a model for other genetically dominant diseases.
Symptoms of the disease can vary between individuals and among affected members of the same family, but the symptoms progress predictably for most individuals. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years after symptoms begin. There is no cure for HD, and full-time care is required in the later stages of the disease. Emerging treatments can relieve some of its symptoms.
Self-help support organizations, first founded in the 1960s and increasing in number, have been working to increase public awareness, to provide support for individuals and their families, and to promote research. The Hereditary Disease Foundation, a research group born out of the first support organization, was instrumental in finding the gene in 1993. Since that time, many new research discoveries have been made and understanding of the disease is improving. Current research directions include determining the exact mechanism of the disease, improving animal models to expedite research, clinical trials of pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with the goal of repairing damage caused by the disease.
Signs and symptoms
Symptoms of Huntington’s disease commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age. In the early stages, there are subtle changes in personality, cognition, and physical skills. The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages. Almost everyone with Huntington’s disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking. Eating difficulties commonly cause weight loss and may lead to malnutrition. Sleep disturbances are also associated symptoms. Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.
Reported prevalences of behavioral and psychiatric symptoms in Huntington’s disease
Depressed mood 33–69%
Obsessive and compulsive 10–52%
Cognitive abilities are impaired progressively. Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions. As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one’s life), procedural (memory of the body of how to perform an activity) and working memory. Cognitive problems tend to worsen over time, ultimately leading to dementia. This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g. Alzheimer’s disease.
Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality. Difficulties in recognizing other people’s negative expressions have also been observed.
The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%. For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization. Suicidal thoughts and suicide attempts are more common than in the general population.
Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.
Stem Cell Therapy:
Stem cell therapy has been experimentally used with resistant cases of Huntington’s Disease. The actions of the therapy appear to be directed toward immune modulation (reducing the autoimmune component), anti-inflammatory responses and ultimately regeneration of the schwan cells. This result is amplification of the neural signals secondary to increased or repaired myelin. We feel that the progressive form, once causal agents are excluded, may be an excellent candidate for this therapy. The literature supports the high incidence of failure with conventional therapy and the limited trials are more than suggestive of a life saving potential.
After a review of your medical records and discussions with medical staff, a protocol is designed especially for you. Specifics of your condition are addressed along with any special needs. It may be similar to the one illustrated below:
At the clinic you will be examined by our physicians. Information including any risks and expectations concerning your treatment, plus answers to any questions you may have will be addressed. A blood draw, to determine cell counts and other chemistries will be collected and cell expansion medication may be administered. Then you will return to your hotel for a restful day or a good nights sleep.
At the clinic our physician/s will review the laboratory results, determine if the cell count is within range, and discuss the response to the stimulation. They may or may not provide additional cell expansion medications and may add adjunctive treatments. The levels of your response will determine if you would return to the hotel, with little restriction on your activities, or possibly go forward with harvesting and processing your cells.
If the cell count and viability is appropriate for harvest either a bone marrow or adipose collection will be utilized. We typically use local anesthetics for adults and general anesthesia for youngsters. The entire harvest procedure normally takes less than 30 minutes. Although some pain is felt when the needle is inserted, most patients do not find the bone marrow or adipose collection procedure particularly painful.
We recently placed a number of videos on our website interviewing our patient’s who discuss the procedure and their lack of discomfort.
After the collection you may return to the hotel, with some restrictions. The bone marrow or adipose collected is processed in our contract State-Of-Art laboratory by trained staff, under the supervision of the lab physician.
As an alternative to the above, cord blood may be used based on the patient’s individual medical condition and options.
At the clinic or at the hospital you will be treated by IV infusion and a lumbar puncture, which injects the stem cells into the cerebrospinal fluid. This route transports the cells into the spinal canal and the brain directly influencing the nervous systems, thereby eliminating the brain/blood barrier. If a lumbar puncture is performed, the patient will be required to restrict their activities and potentially spend the day in the hospital or at their hotel.
At the clinic or hospital the patient will receive a post-treatment examination and evaluation prior to their release. Additional therapy and treatments may also be utilized to maximize the placement and activities of the procedure.
Day 6: Optionally there may be the use of additional ancillary therapies to enhance the procedure.
What makes our treatment different ?
Our approach includes stimulation, prior to collection, processing and expansion of the cell along with the use of growth factors, together with an integrated medical approach. This maximizes the growth and implantation potentials yielding optimized potentials of making changes in your disease.
Our staff physicians are all board certified, in their field with years of experience. Your team includes both primary and ancillary care professionals devoted to maximizing your benefits from the procedures. We enroll you in an open registry to track your changes independently, for up to 20 years.
As our patient we also keep you abreast of the newest developments in stem cell research. This is an ongoing relationship to maintain and enhance your health.
Our promise is to provide you with travel and lodging support, access to bilingual staff members throughout the entire process and most importantly the best medical care possible.
References and Articles:
THURSDAY, JANUARY 5, 2012
The promising research described in this paper was funded in large part by a CIRM Early Translational grant to Nolta, which has the goal of developing a combination cell and gene therapy candidate to treat Huntington’s Disease, a devastating neurological disease for which there is no effective treatment. Among those who have suffered and died from Huntington’s is one of my favorite songwriters, Woody Guthrie, whose 100th birthday will be celebrated in July. There’s more information about Huntington’s disease and awards we’ve funded available on our website.
In Huntington’s Disease, a mutated form of a protein called huntingtin causes certain neurons in the brain to die. The goal of Nolta’s award is to use stem cells to disable the ability of those neurons to make the disease-causing protein. In their paper, Nolta and colleagues show that a type of stem cell found in the bone marrow called mesenchymal stem cells (MSCs) can be engineered to produce a molecule that inhibits the production of the mutated huntingtin protein. They show, in a petri dish, that this molecule is secreted by the stem cells, is taken up by nearby neuronal cells, and reduces the amount of the disease-causing protein produced by those cells. The next important step will be testing these engineered stem cells in an animal model of Huntington’s.
Stem cell researchers inch toward treatment for Huntington’s Disease
June 17, 2010 | By Susan Valot | KPCC
People with Huntington’s disease face an awful future – perhaps 20 years as it slowly strips away brain cells.
But there’s a chance that in the next 20 years, researchers at UC Irvine could develop treatments that could arrest Huntington’s – and other brain and nervous systems disorders – thanks in part to a girl from Fountain Valley.
Emily Krull of Fountain Valley was a normal, brown-haired little girl. Up until sixth grade, she got good grades and made the honor roll. But seventh grade hit and Emily’s grades plummeted. She became depressed and hard to motivate.
Her parents had adopted Emily when she was little; they figured whatever was going on was just a teenage phase. But then Emily started blinking a lot and losing her balance, like she was drunk.
Her mom, Carla Krull, says Emily’s school even wanted to give her a drug test at her prom.
“And when she went to Knott’s Scary Farm, they wanted to alcohol test her,” Carla Krull remembers. “And imagine, you’re with your friends or your boyfriend and how the humiliation of having to be drug tested, and they’re not listening to you when you say, ‘I’m not drunk.'”
Emily’s parents knew something was wrong. They just didn’t know what.
Eight neurologists later, they figured it out: Huntington’s Disease – the fatal genetic brain disorder. Brain cells stop communicating and die off.
Folk singer Woody Guthrie died of Huntington’s. So did Emily Krull, last October at the age of 21.
But Carla Krull says before she died, Emily walked into a lab at UC Irvine and donated a small chunk of skin. From Emily’s skin, researchers are developing stem cells that might someday help lead to a cure for Huntington’s.
“It was a real exciting day for her,” Carla Krull said. “It was like a war wound. It’s like the movie, ‘Twilight,’ the vampires? It was like her vampire bite. Yeah, she was very excited about it.”
The lab that Emily walked into is run by Leslie Thompson, who’s studying possible stem cell treatments for Huntington’s Disease, which is in some ways similar to Parkinson’s or Alzheimer’s disease. The brain’s pathways are blocked by clumps of protein.
“The cells don’t communicate well. They don’t turn over. They don’t clear out garbage, like the cell debris. They can’t clear it as well,” Thompson said. “They can’t create the appropriate proteins, the correct signals between the neuron and the brain. They can’t make enough of them that they would normally need to make.”
Similarities in Huntington’s, Parkinson’s, Alzheimer’s and Lou Gehrig’s disease mean there’s overlap in research. A breakthrough in Huntington’s could help move along research into the other brain-robbing diseases.
With Huntington’s, Thompson says it’s a little bit easier because scientists know it’s caused by a single genetic mutation.
“Which offers a huge advantage for this kind of work, because you know who has it – you know exactly what individuals have it, you know when they become symptomatic or who’s going to become symptomatic so you can start treatment early. You can create lines that all have the genetic mutation in them,” said Thompson.
If one of your parents had Huntington’s – which usually strikes between the ages of 35 and 44 – then you have a 50 percent chance of getting it.
Thompson is working on creating models that use Huntington’s Disease stem cell lines so researchers can more quickly test which drugs work.
She’s also looking at how mice with Huntington’s Disease react when neural stem cells are injected into their brains.
“The stem cells produce very protective factors to the brain and so if we transplant these cells, certain types of cells, into the brain of, say an HD [Huntington’s Disease] mouse, which is what we’re doing right now, they sort of nurse existing neurons that are there and keep them sort of protected,” Thompson said.
That suggests a treatment someday that could stop symptoms from progressing or prevent them in the first place. But Thompson says there’s still a lot they don’t know.
“What are some of the initial triggers?” she said. “We know a lot about some of the things that happen in the neuron. But we’re still at the phase of trying to prevent some of the really early steps and you know, how to get a neuron that’s sick to not be sick, basically.”
Thompson predicts tests on stem cell-based therapies for Huntington’s Disease could start in the next five to 15 years. That’s something that gives hope to Emily Krull’s parents. Comment: Because of the limited time frame from diagnosis to death perhaps the better way to approach this disorder would be to utilize the current level of knowledge for the disorder, via stem cell treatment now. The potential with the use of autologus stem cells is amazing high with a very low risk.
“I feel that she was meant for us because we would carry this on. And we’re determined to carry this on until we get a cure.”
And, says mom Carla Krull, if Emily could see the progress that’s been made in the past couple of years toward finding a treatment for Huntington’s Disease, Emily would be smiling.
A Potential Treatment for HD Using MSCs Future cellular therapies using MSCs would involve delivering MSCs into the brain, which has been approached in a number of different ways. Scientists have proposed delivering MSCs through an injection directly into the brain, an injection into the space surrounding the spinal cord, or a route through the nose (e.g. a nasal spray).
Although clinical trials using MSCs in humans have not yet been approved in the United States, one human cellular therapy trial has been conducted in France. In the trial, neural stem cells rather than MSCs were used. Five patients with HD received transplants from human fetal neural stem cells. After two years, three out of the five patients demonstrated motor and cognitive improvements. While this experiment provides hopeful evidence that stem cell therapies may provide a treatment for HD, the results should be interpreted with caution. First, two of the patients did not show significant improvements. Second, as noted before, neural stem cells and MSCs have different characteristics. Therefore, the results from this experiment do not indicate whether MSCs would provide an effective treatment. Finally, after four to six years, the patients showed clinical decline once again, suggesting that additional research is required before an effective long-term treatment is developed.
Extensive biological safety trials have been conducted with MSCs by Dr. Gerhard Bauer and Dr. Jan Nolta at University of California at Davis. They have performed numerous experiments over the past decade on different animal models including mice, rats, and primates, to test if MSCs can be safely injected or grafted without tumorous growths. Additionally, a successful clinical trial in France with five HD patients suggests that transplantation of stem cells into the brain can be done without negative health consequences. However, more evidence for the biological safety of injecting MSCs into the brain is needed to meet the rigorous safety standards of the FDA in the United States
Comment: After over 20 years of safe applications with single lines or autologus stem cells it seems prudent to proceed with clinical applications. The long term use in a variety of neruodegenerative disorders has been occurring in both the clinical trials arena and the clinics overseas, with minimal adverse events. Patients who have limited time and appear to respond to this high ratio of potential benefit to risk procedure should consider this as a therapy. Even the palliative nature of the multi year relief seen by the French patients may allow for the time necessary to achieve the means necessary to manipulate the genes into proper alignment.
Nonmyeloablative Autologous Hematopeietic Stem Cell Transplantaion for Refractory CIDP American Academy of Neurology March 11, 2009 Y. Oyama, MD etal
Most patients with chronic inflammatory demyelinating polyneuropathy (CIDP) initially respond to corticosteroids, immunosuppressive drugs, IV immune globulin (IVIg), and plasma ex- change (PE). However, more than half relapse, with some developing a recurrent or persistent clinical course resulting in severe disability and even death. Nonmyeloablative autologous hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases has demonstrated promising results, with reports of durable remissions and lower toxicity compared to myeloablaive HSCT. Herein, we report the first patient treated in a phase I trial of autologous HSCT utilizing a nonmyeloablative regimen for refractory CIDP.
Results. The patient was a 32-year-old woman who presented with gradual onset of paresthesia and twitching of the face and limbs, and progressive weakness of both upper extremities, evolving over several weeks to include her lower extremities as well. She was areflexic with weakness more marked proximally and in the upper extremities. Based on nerve conduction studies consistent with a demyelinating polyneuropathy, she was treated with IVIg weekly for 5 weeks with clinical improvement. However, when this was reduced in frequency, weakness recurred and she was commenced on daily/alternate-day PE, to which she responded. Attempts to taper PE resulted in worsened neurologic symptoms, which progressed despite addition of prednisone (80 mg/day). A 3-month trial of methotrexate was complicated by anemia. She was maintained on twice-weekly PE but this was complicated by three episodes of pheresis catheter-related bacteremia and resultant disease exacerbations. MMF was then added with unsatisfactory result. During periods of exacerbation, she was unable to raise her arms against gravity or handle objects steadily, and could not ambulate more than 30 meters or climb stairs. Despite maintenance PE, the patient continued to have recurrent exacerbations and line infections resulting in referral for HSCT 30 months after disease onset.
HSCT was generally well-tolerated with no unexpected non-hematologic toxicities. Neutrophil counts recovered by day 11; platelet counts by day 9 after HSCT. She was successfully weaned off PE corticosteriods and IVIg and gradual taper of MMF. She has had no disease exacerbations since HSCT, with a follow-up of 22 months. Clinical improvement has been gradual but definite, and by 6 months post-transplant, her upper extremity strength had improved and she could ambulate and climb stairs. Rankin functional score improved from 4 to 1.
Chronic inflammatory demyelinating polyneuropathies: current treatment strategies. Curr Neurol Neurosci Rep.
Department of Neurology, Weill Medical College of Cornell University, Peripheral Neuropathy Center, New York, NY 10022, USA.
Chronic inflammatory demyelinating polyradiculopathy (CIDP), considered an immune-mediated disease, is likely under-recognized and under-treated due to its heterogeneous presentation and the limitations of clinical, serologic, and electrophysiologic diagnostic criteria.
Despite these limitations, early diagnosis and treatment is important in preventing irreversible axonal loss and improving functional recovery. Primary treatment modalities include intravenous immunoglobulin and plasmapheresis, for which there is randomized, double-blind, placebo-controlled evidence. In addition, despite less definitive published evidence of efficacy, corticosteroids are considered standard therapies because of their long history of use. Studies have failed to demonstrate a difference in efficacy among these three treatments; consequently, the choice is usually based on availability and side-effect profile. A number of chemotherapeutic and immunosuppressive agents have also shown to be effective in treating CIDP but significant evidence is lacking; therefore, these agents are primarily used in conjunction with other modalities. Regardless of the treatment choice, long-term therapy is required to maintain a response and prevent relapse.
Comment: Note the failure of and need for lifelong therapy vs the use of stem cell therapy, above. The need for these life saving proceedures seems obvious for a select population and at World Stem Cells Clinic we are inclined to use cutting edge techniques to aid those individuals.
I have grade IV osteoarthritis (severe loss of cartilage leading to bone rubbing on bone) of my right hip. I have seen 3 orthopedic doctors, all of which have said I need to have surgery for hip replacement. Additional options for treatment were limited. As a nurse, and at my age, having seen both good and bad outcomes following hip replacement, and also knowing hip replacement is not without risk, I chose to seek other options of treatment for myself.Read more
Andrew is thriving. We have seen and continue to see major improvements. He has matured beyond anything I can explain (I have had to rapidly adjust my parenting as I now have a much older & more sophisticated child), his comprehension (perhaps better to say his ability to express and act upon his comprehension) is now age appropriate.Read more
Hello, When we came from Cancun the first week we noticed an improvement in eye contact. It improved about 70%. His attention improved about 50% and he was more in our world when it comes to understand what it happening around him. He lost some of his attention for the last two weeks but it is still better than it was prior stem cells and even Janik BIs therapist say it is easier to work with Janik in ABA because his eye contact is better and his focus is also better."Read more
Well Owen is happy again, which is the biggest improvement. He is laughing and giggling again. His eye contact has improved and he is playing with toys again. All of these things had stopped. I`m so happy that he is happy. ( His Mom)Read more
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This is your opportunity to start stem cell treatments i