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Advancements in the treatment of Huntington’s Disease: pharmacologic treatments vs. surgical intervention Master’s Presentation Marsee Huffman March 22, 2007 Epidemiology Huntington’s Disease A genetic neurodegenerative disorder caused by a dominant trait Affects approximately 1 in 10,000 individuals, varying between countries and racial groups. Average age of onset is 40 years old, although, this can very from two years old to the elderly. Spread genetically and doesn’t skip generations. Pathophysiology Age of onset of disease varies – Can be determined by the number of CAG (glutamine) repeats found on gene 4 More repeats = Earlier onset – The number of repeats can also provide insight into the possible severity of the disease More repeats = More severe pathology – Normally, if the patient develops the first symptoms at a very young age the disease will progress much quicker than if it were to appear in a patient’s older years Pathophysiology The first symptoms usually present as the patient seeming lazy or unmotivated. Three Clinical Features: – Motor Impairments – Cognitive Deficits – Psychiatric Changes Motor Impairments Most apparent symptom! Speech can become stuttered or slurred In earliest stage choreic movements appear in the fingers, gives appearance of being nervous or fidgety – Choreic movements involuntary twitching or jerking in muscle groups not associated with the production of definite purposeful movements In later stages patients lose coordination Cognitive Deficits Not the most apparent in early stages May appear they are just forgetting things They may lose the ability to manage finances or their ability to concentrate for long periods of time Psychiatric Changes A wide range of changes can occur. These can include: – Irritability – Violent Anger – Paranoia – Depression – Apathy – Anxiety Most troublesome on family and friends Psychiatric Changes Patients can also develop certain mental disorders – Major depression disorder – Bipolar disorder – Obsessive-compulsive disorder Current Treatments No cure for Huntington’s Disease as of yet. Effective non-pharmacologic treatments include: – Supplements – Exercise – Proper Diet Current Treatments Motor Impairments – Mainly non-pharmacologic treatment initially Ankle weights to reduce amplitude of movements – Once voluntary movements are hindered the goal is to treat underlying anxieties Neuroleptics (haliperidol, risperidone) Benzodiazepines (clonazepam, diazepam) Dopamine depleting agents (reserpine, tetrabenazine) Current Treatments Cognitive Impairments – Mainly non-pharmacologic Making lists Maintaining routines Family/Friends should modify their conversation; i.e. avoid open-ended questions and use short, less complex sentences, etc. Current Treatments Psychiatric Changes – Possibly the easiest symptom to treat – Goal is to treat symptoms/disorder pt is experiencing – Pharmacologic Measures: SSRIs (fluoxetine, paroxetine) Tricyclics (nortriptyline) Nefazodone, Buproprion, and Venlafaxine Clinical Question Could the use of pharmacologic measures to inhibit the polyglutamine-mediated aggregation in the affected Huntington’s patient be superior to the use of neuronal cell replacement to delay the onset or halt progression of the disease? Possible new treatments Research suggests: – Prohibiting protein aggregation by the mutant gene – Neuronal cell implants Inhibition of aggregation The pathological hallmark of Huntington’s disease is the aggregation of a mutant polyglutamine protein (multiple CAG repeats) – About 35-45 repeats Goal = halt the aggregation of the mutant (polyglutamine) protein htt Wang, et al. Studied several FDA approved compounds that contained known aggregation inhibition properties After in vitro experimentation 10 compounds were identified as the most potent aggregation inhibitors Wang, et al. These 10 were then tested in Hdh knock-in mice to determine effectiveness at arresting the mutant huntington protein – Most potent inhibitors found to arrest mutant protein Celastrol used in rheumatoid arthritis treatment Juglone used for antihemorrhagic and antifungal proerties Skogen, et al. Specifically studied the affects of a specific group of the oligonucleotide (ODN) class in vitro – Oligonucleotide = short sequences of nucleotides (RNA or DNA), typically with twenty or fewer bases The specific ODN, GRO HDG, has been previously shown to block protein function Skogen, et al. Researchers studied several types of oligonucleotides – Including: HDA, HDB, HDC, HDG They found the most potent aggregate inhibitor was the G-rich oligonucleotide HDG – Inhibition was almost as potent as that seen in the control group Skogen, et al. • ODNs have been used in previous clinical trials and they show no significant adverse effects, even at higher doses – The team concluded that there is a good possibility of this therapy being successful in clinical trails Neuronal Cell Implants Another potential approach to treating Huntington’s is the use of neuronal cell implants Neuronal Cell Implants Treatment focuses on replacing damaged striatal cells using fetal striatal tissue Primate studies have been conducted initially to view the benefits of this type of therapy Clinical studies have also been conducted in Europe, in limited groups Kendall, et al. Transplants in primate models Researchers theorized possible hardships that may present: – Adequate maturation of grafted tissue – Regeneration of host axonal afferents – Directed outgrowth of axons from grafted tissue Kendall, et al. Using imaging techniques researchers determined proper maturation Diffuse axonal systems grow into the graft and connect, but is only partial in areas such as the cerebral cortex or the thalamus Electrophysiological recordings showed that a functional reconnection was made in transplants from grafted tissue Bachoud-Levi, et al. Study conducted in Europe on 5 HD patients in various stages on disease progression Patients involved received striatal neuronal fetal cell implantation and were followed until endpoint (3 years) – Results varied One patient in advance stages experienced immunosuppression and subdural hermorrhages after implantation Another patient experienced only 10 mos of symptom alleviation after first implantation and only 7 mos after a second Remaining 3 patients experienced positive benefits up to 3 years after implantation (when study was published); a 6 year study is being conducted and expected to be published soon Bachoud-Levi, et al. Benefits of surgery – Reversal of motor, functional, and cognitive dysfunctions caused by disease Drawbacks – Appears to be only beneficial to certain patients – Study only conducted on five patients Conclusions Pharmacologic measures have shown to be affective in inhibiting protein aggregation in vivo – However, there has not been sufficient research conducted to be able to determine possible benefits in clinical trial Conclusions Neuronal cell implantation has shown benefits in selected patients in clinical trial and enthusiasm about this avenue of treatment seems to be increasing – However, there have not been enough clinical trials/patients to be able to speculate how many patients this treatment could possibly benefit Conclusions A lot more research needs to be done in order to be able to properly treat these patients and have a positive outcome from this disease. References Brasted, P., Watts, C, Robbins, TW, Dunnett, SB (1999). "Associative plasticity in striatal transplants." 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