Transcript New treatments for Huntington`s Disease

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
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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
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More repeats = Earlier onset
– The number of repeats can also provide insight into the
possible severity of the disease
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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
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The first symptoms usually present as the
patient seeming lazy or unmotivated.
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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
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In later stages patients lose coordination
Cognitive Deficits
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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
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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:
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– Supplements
– Exercise
– Proper Diet
Current Treatments
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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
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Neuroleptics (haliperidol, risperidone)
Benzodiazepines (clonazepam, diazepam)
Dopamine depleting agents (reserpine,
tetrabenazine)
Current Treatments
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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
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Psychiatric Changes
– Possibly the easiest symptom to treat
– Goal is to treat symptoms/disorder pt is
experiencing
– Pharmacologic Measures:
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SSRIs (fluoxetine, paroxetine)
Tricyclics (nortriptyline)
Nefazodone, Buproprion, and Venlafaxine
Clinical Question
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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
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Research suggests:
– Prohibiting protein aggregation by the mutant
gene
– Neuronal cell implants
Inhibition of aggregation
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The pathological hallmark of Huntington’s
disease is the aggregation of a mutant
polyglutamine protein (multiple CAG
repeats)
– About 35-45 repeats
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Goal = halt the aggregation of the mutant
(polyglutamine) protein htt
Wang, et al.
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Studied several FDA approved compounds
that contained known aggregation inhibition
properties
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After in vitro experimentation 10
compounds were identified as the most
potent aggregation inhibitors
Wang, et al.
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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
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Celastrol  used in rheumatoid arthritis treatment
Juglone used for antihemorrhagic and antifungal
proerties
Skogen, et al.
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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
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The specific ODN, GRO HDG, has been
previously shown to block protein function
Skogen, et al.
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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
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Another potential approach to treating
Huntington’s is the use of neuronal cell
implants
Neuronal Cell Implants
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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.
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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.
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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.
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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
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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.
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Benefits of surgery
– Reversal of motor, functional, and cognitive
dysfunctions caused by disease
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Drawbacks
– Appears to be only beneficial to certain patients
– Study only conducted on five patients
Conclusions
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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
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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
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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
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Proc. Natl. Acad. Sci USA 96: 6.
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Harper SQ, S. P., He X, Eliason SL, Marins IH, Mao Q, et. al. (2005). "RNA interference improves motor
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Imbriglio, Suzanne (1992). "Huntington’s disease at mid-stage." Clinical Management.
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