Therapy for Huntington’s
Disease
Dr. Rahul Kumar,
Senior Resident, Department of Neurology,
M S R Medical College
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Huntington’s Disease
Anatomy of the Basal Ganglia
Functions of the Basal Ganglia
• Non-Motor Loops
– Executive/Prefrontal Loop
– Limbic Loop
– Oculomotor Loop

• Motor Loop...
Pathways of Motor Loop
• Direct Pathway
– Overall Excitatory

• Indirect Pathway
– Overall Inhibitory
Direct Pathway
(aka the Express Route)
CORTEX
Glutamate (+)

PUTAMEN
Glutamate (+)

GABA (-)

(GPe)
(STN)

GP interna
GABA...
Indirect Pathway
(aka, scenic route)
CORTEX
Glutamate (+)

PUTAMEN
GABA (-)

GP externa
Glutamate (+)

GABA (-)

STN
Gluta...
Huntington’s Disease
CORTEX
Glutamate (+)

PUTAMEN
GABA (-)

GP externa
Glutamate (+)

GABA (-)

STN
Glutamate (+)

GP int...
Symptom
Chorea

Drug

Considerations

Tiapride†

Good effectiveness with few adverse effects

Pimozide

Moderately effecti...
Voluntary motor impairment

Hypokineticrigid patients

Antiparkinsonian
medication
(levodopa, dopamine
agonists,
anticholi...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Behavioural symptoms
Depression

Frequent adverse effects. These drugs might worsen
chorea via their effect on increasing ...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Therapy Services:

Degenerative Disease Model
•

Supportive treatment with attention to psychosocial issues and
community ...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Downstream targets for therapeutics
for Huntington’s disease
Sweet Relief for Huntington
Disease

Masahisa Katsuno; Hiroaki Adachi;
Gen SobueNat Med 10(2):123-124, 2004.
© 2004 Nature...
Mechanisms of Disease: Histone
Modifications in Huntington's
Disease
Ghazaleh Sadri-Vakili; Jang-Ho J Cha
Nat Clin Pract N...
• “The use of HDAC inhibitors and other
therapies that target gene transcription is an
exciting development in the field o...
Creatine and HD
• Creatine is a critical element in cellular energy production and modulation.
It is the substrate of the ...
Proposed Creatine Study:

Creatine Safety, Tolerability, & Efficacy In
Huntington’s Disease (CREST-E)

Randomized, double-...
Energy Depleting Enzyme May Be
Target for Huntington's Drugs
Chem Biol 2006;13:1-6
• While PARP1 is essential for the repair of damaged
DNA, we also know that, if overactivated, it can
cause cell death by ...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Goals of Therapy
• To treat the motor manifestations
• To treat the psychiatric manifestations
• Supportive therapy
• To h...
Neuron Transplant Stabilizes
Huntington's Disease for Several
Years
The Lancet Neurology on February
27, 2007
• "Neuroprotection could stop the disease," they
conclude, "but only a graft can restore lost
function."
Stem and progenitor cells of
the adult human nervous
system
Isolation and purification of neural progenitor cells
Induced neurogenesis for treating
neurodegenerative disorders

LV : lateral ventricle
CC : corpus
callosum
DG : dentate gy...
Summary…..
Huntingtin-interacting Proteins
Nat Genet. 2005 Apr 3; [Epub ahead of print]

A genomic screen in yeast implicates kynurenine 3-monooxygenase as a
therape...
Animal models
Destruction of striatal spiny neurons
Sparing interneurons containing:
Somatostatin
Neuropeptid Y
NADPH-diap...
Treatment: Supportive
PHARMACOLOGIC
• Choreic movements may be partially
suppressed by neuroleptics
(Tetrabenazine, Respir...
Research: Huntington Study
Group (HSG)
At-Risk & Observational Research StudiesRepository of data including blood/biologic...
Human Clinical Trials:
Huntington Study Group
• Compounds must cross blood-brain barrier
• Research focus on finding poten...
Striatal Input and
Output
1
1
What is missing?
– Effect of DA on pathways
• Direct Pathway: Stimulates
• Indirect Pathway: Inhibits
• Overall Excitatory
DA in Direct Pathway

Dopamine (+)
Substantia Nigra
pars compacta
DA in the Indirect Pathway

Dopamine (-)
Substantia Nigra
pars compacta
How do I keep this all straight?
• Basal Ganglia (Caudate, Putamen, and GP)
– Medium Spiny neurons = GABAergic
• GABA = In...
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
Huntington's Disease, Potential Therapies
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Huntington's Disease, Potential Therapies

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Treatment options for Huntingtons Disease, Potential Targets.

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  • Autosomal Dominant, Chromosome 4
    Huntingtin protein
    Loss of striatal neurons
    Early
    Change in personality, intellect
    Chorea/athetosis
    Late findings
    Akinesia Vegetative
  • Striatum: caudate and putamen
    Make up what type of nuclei? (input)
    Globus Pallidus interna and substantia nigra pars reticulata
    Make up what type of nuclei? (output)
    Globus pallidus externa, STN, and substantia nigra pars compacta
    make up what nuclei? (intermediate)
  • Executive loop: involves dorsolateral prefrontal cortex and part of the caudate
    Limbic loop: involves cingulate cortex and nucleus accumbens
    Oculomotor loop: involves cadate and superior colliculus (responsible for eliciting rapid eye movements called saccades)
    Focus here on the motor loop, (the other loops are similar so if we learn this now it should help demystify the others)
    BG influences movement by regulating upper motor neurons-necessary for normal initiation of voluntary movement
    Responds in anticipation of and during movements
  • Balance between the two are not well-defined, but they work together for movement. While they are presented separately here, keep in mind they are working simultaneously.
  • Overall Excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement)
  • Overall inhibitory. Serves to modulate the disinihibitory actions of the direct pathway
  • 這張卡通圖說明了成人腦內有的基本的progenitor cell和它們的直系關係
    紅色的細胞是neural stem cell,它會分化成至少三種的progenitor cell,就是藍色的那三個細胞,它們會再分化成放大神經傳導的細胞等
    紫色的是神經細胞,綠色的是Oligodendrocyte,橘色的是Astrocyte
  • 這張圖用來說明如何從人類的組織中,純化出所需要的progenitor cell。
    圖示中主要使用兩種方式來分類,第一種是FACS:fluorescence activated cell sorting,利用plasmid或viral based的EGFP基因送進細胞裡,之後再用FACS系統把GFP陽性的細胞,也就是需要的progenitor cell分類出來。
    第二種是MACS:magnetic cell sorting,利用所需的progenitor cell表面抗原相對應的抗體,在抗體上有磁性物質,如此便可分出需要的細胞。
    得到所需要的progenitor cell後,再去進行實驗。
  • 這張圖是老鼠的腦部,當補償作用和誘發補充神經元時,那些元始細胞的所在
    圖a是新皮質的情形。圖b是海馬體的情形。
    藍色的數字是發生補償作用的地方,紅色的數字是誘發的地方。
    1.中風後和Huntington’s patients補充神經元的地方
    2.大腦皮質剝離
    3.缺血性神經壞死
    4.Alzeimer patients
    5.過度表現的brain-derived neurotrophic factor (BDNF)/noggin而產生誘發神經分化
    6.也是BDNF產生誘發的
    7.是IGF1誘發的
  • Input to striatum
    Medium spiny neurons are the projection neurons of the striatum
    MSNs have large dendritic trees that can integrate inputs from a variety of cortical, thalamic, and brainstem structures, so this makes them a good target.
    One cortical pyramidal neuron will synapse with only one MSN, however MSNs are capable of receiving input from 100s of neurons.
    MSNs also receive info from DA neurons of the substantia nigra and local circuits.
    Integration of inputs is important bc it allows regulation of movement and also permits summation of the subthreshold stimuli in the CNS that we discussed earlier in the course.
    MSNs occur in clusters called striosomes or in the surrounding matrix.
    SMNs are normally quiescent and require simultaneous stimulation from cortical and nigral neurons to become active. The NT SMNs release is GABA, which is inhibitory here.
    The globus pallidus and substantia nigra also use GABA, but in contrast to the striatum are tonically inhibiting (rather than quiescent) on the superior colliculus or thalamus
    In contrast, keep in mind that the cortex, STN, and thalamus make glutamatergic (excitatory) synapses in the motor loops we will be discussing.
    Medium spiny neurons
    In striatum
    Normally quiescent
    Are GABAergic
    Projections from GP and SN are tonically inhibiting, also use GABA
    However, the Cortex, STN, and Thalamus use glutamate (excitatory)
  • DA stimulates the direct pathway and inhibits the indirect pathway for an overall excitatory effect.
    DA input is needed for stimulation of the putamen, along with input from the cortex.
  • Predominantly D1-receptors
  • Predominantly D2-Receptors
  • Huntington's Disease, Potential Therapies

    1. 1. Therapy for Huntington’s Disease Dr. Rahul Kumar, Senior Resident, Department of Neurology, M S R Medical College
    2. 2. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    3. 3. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    4. 4. Huntington’s Disease
    5. 5. Anatomy of the Basal Ganglia
    6. 6. Functions of the Basal Ganglia • Non-Motor Loops – Executive/Prefrontal Loop – Limbic Loop – Oculomotor Loop • Motor Loop (Focus of our journey) – Regulation of upper motor neurons – Necessary for normal initiation
    7. 7. Pathways of Motor Loop • Direct Pathway – Overall Excitatory • Indirect Pathway – Overall Inhibitory
    8. 8. Direct Pathway (aka the Express Route) CORTEX Glutamate (+) PUTAMEN Glutamate (+) GABA (-) (GPe) (STN) GP interna GABA (-) VA/VL THALAMUS
    9. 9. Indirect Pathway (aka, scenic route) CORTEX Glutamate (+) PUTAMEN GABA (-) GP externa Glutamate (+) GABA (-) STN Glutamate (+) GP interna GABA (-) VA/VL THALAMUS
    10. 10. Huntington’s Disease CORTEX Glutamate (+) PUTAMEN GABA (-) GP externa Glutamate (+) GABA (-) STN Glutamate (+) GP interna GABA (-) VA/VL THALAMUS +
    11. 11. Symptom Chorea Drug Considerations Tiapride† Good effectiveness with few adverse effects Pimozide Moderately effective, few adverse effects Haloperidol Moderately effective, moderate adverse effects (sedation, EPS) Tetrabenazine† Effective but frequent adverse effects (depression, EPS) Phenothiazines Moderately effective, considerable adverse effects (EPS, anticholinergic reactions, immunological responses)
    12. 12. Voluntary motor impairment Hypokineticrigid patients Antiparkinsonian medication (levodopa, dopamine agonists, anticholinergics) Generally less effective than in patients with Parkinson's disease. Adverse effects include induction or aggravation of chorea and mood disturbances (aggression, psychosis) Choreic patients with hypokinetic symptoms No specific drug options Antipsychotics should be avoided if possible as further impairment of voluntary movements aggravates functional disability
    13. 13. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    14. 14. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    15. 15. Behavioural symptoms Depression Frequent adverse effects. These drugs might worsen chorea via their effect on increasing brain dopamine levels Benzodiazepines - Amitriptyline Possibly beneficial in depression-related anxiety Benzodiazepines - Antipsychotics Especially those with sedative effects (e.g. haloperidol) Propranolol, pindolol† Psychosis Anorectic adverse effects might theoretically accelerate bodyweight loss Monoamine oxidase inhibitors Irritability, aggression Agents with few anticholinergic adverse effects are preferred (e.g. desipramine†). Response is likely to be incomplete because of dose-limiting adverse reactions SSRIs Anxiety Tricyclic antidepressants Paradoxical aggravation of aggression has occasionally been reported in patients with Huntington's disease Classical antipsychotics Depot preparations might be helpful in noncompliant patients Clozapine Useful for treatment-resistant psychosis and patients with marked hypokinetic symptoms
    16. 16. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    17. 17. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    18. 18. Therapy Services: Degenerative Disease Model • Supportive treatment with attention to psychosocial issues and community and home care services. • speech intelligibility and functional communication strategies, cognitive-behavioral strategies, swallowing, caregiver education and training • PT: balance/gait, joint range, muscle strength & aerobic capacity, dystonia management, adaptive equipment for safety. • OT for to maximize functional independence with ADLs, adaptive feeding equipment.
    19. 19. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    20. 20. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    21. 21. Downstream targets for therapeutics for Huntington’s disease
    22. 22. Sweet Relief for Huntington Disease Masahisa Katsuno; Hiroaki Adachi; Gen SobueNat Med 10(2):123-124, 2004. © 2004 Nature Publishing Group
    23. 23. Mechanisms of Disease: Histone Modifications in Huntington's Disease Ghazaleh Sadri-Vakili; Jang-Ho J Cha Nat Clin Pract Neurol. 2006;2(6):330-338. ©2006 Nature Publishing Group
    24. 24. • “The use of HDAC inhibitors and other therapies that target gene transcription is an exciting development in the field of HD therapeutics. There are strong indications that HDAC inhibitors might be of therapeutic benefit in HD, but their precise mechanism of action has yet to be determined.”
    25. 25. Creatine and HD • Creatine is a critical element in cellular energy production and modulation. It is the substrate of the creatine kinase system which helps prolong cellular life and protect against cell injury and death. • Hersh et al. Neurology 2006, Randomized, double-blind, placebocontrolled study in 64 subjects with HD, 8 g/day of creatine administered x 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. • BIOMARKER: Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment. • Dose escalation study revealed 30g/day creatine as optimal dose for sustained suppression of 80H2’dG to normal levels and sustained reduction in brain atrophy on MRI morphometry.
    26. 26. Proposed Creatine Study: Creatine Safety, Tolerability, & Efficacy In Huntington’s Disease (CREST-E) Randomized, double-blinded, placebo controlled trial of 30 grams of creatine/day x 36 months in early symptomatic patients with HD proposed to test hypothesis that creatine will slow progressive functional decline in HD.
    27. 27. Energy Depleting Enzyme May Be Target for Huntington's Drugs Chem Biol 2006;13:1-6
    28. 28. • While PARP1 is essential for the repair of damaged DNA, we also know that, if overactivated, it can cause cell death by excessive energy depletion. • HD neurons are susceptible to death due to low baseline levels of ATP. When subjected to oxidative stress, the ATP levels fall even further, compromising cell viability. • reatment with K245-14 protected the HD cells from energy loss as well as death
    29. 29. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    30. 30. Goals of Therapy • To treat the motor manifestations • To treat the psychiatric manifestations • Supportive therapy • To halt the progression of the disease ! • To reverse the neurodegenerative process !!!
    31. 31. Neuron Transplant Stabilizes Huntington's Disease for Several Years The Lancet Neurology on February 27, 2007
    32. 32. • "Neuroprotection could stop the disease," they conclude, "but only a graft can restore lost function."
    33. 33. Stem and progenitor cells of the adult human nervous system
    34. 34. Isolation and purification of neural progenitor cells
    35. 35. Induced neurogenesis for treating neurodegenerative disorders LV : lateral ventricle CC : corpus callosum DG : dentate gyrus CA1 : hippocampal CA1 pyramidal cells 3V : third Ventricle SCF : stem cell factor SSRI : serotonin selective reuptake
    36. 36. Summary…..
    37. 37. Huntingtin-interacting Proteins
    38. 38. Nat Genet. 2005 Apr 3; [Epub ahead of print] A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Giorgini F, Guidetti P, Nguyen Q, Bennett SC, Muchowski PJ. Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt), which leads to its aggregation in nuclear and cytoplasmic inclusion bodies. We recently identified 52 loss-of-function mutations in yeast genes that enhance the toxicity of a mutant Htt fragment. Here we report the results from a genome-wide loss-of-function suppressor screen in which we identified 28 gene deletions that suppress toxicity of a mutant Htt fragment. The suppressors are known or predicted to have roles in vesicle transport, vacuolar degradation, transcription and prion-like aggregation. Among the most potent suppressors was Bna4 (kynurenine 3-monooxygenase), an enzyme in the kynurenine pathway of tryptophan degradation that has been linked directly to the pathophysiology of Huntington disease in humans by a mechanism that may involve reactive oxygen species. This finding is suggestive of a conserved mechanism of polyglutamine toxicity from yeast to humans and identifies new candidate therapeutic targets for the treatment of Huntington disease.
    39. 39. Animal models Destruction of striatal spiny neurons Sparing interneurons containing: Somatostatin Neuropeptid Y NADPH-diapohrase/NO synthase positive neurons Tools: Excitotoxin Quinolinic acid Transgenic animals
    40. 40. Treatment: Supportive PHARMACOLOGIC • Choreic movements may be partially suppressed by neuroleptics (Tetrabenazine, Respirdal, Seroquel, Zyprexa, Haldol) or benzodiapines (Valium, Ativan, Klonopin). • Anti-parkinsonian agents may ameliorate rigidity, however, L-dopa compounds (Sinemet) can increase chorea.
    41. 41. Research: Huntington Study Group (HSG) At-Risk & Observational Research StudiesRepository of data including blood/biological samples, genetic testing, UHDRS evaluations, family information, and brain imaging on presymptomatic, symptomatic, and some gene negative subjects – PHAROS: Prospective Huntington at Risk – PREDICT-HD: Neurobiological Predictors of HD – COHORT: Cooperative Huntington’s Observational Research Trial
    42. 42. Human Clinical Trials: Huntington Study Group • Compounds must cross blood-brain barrier • Research focus on finding potential blood or brain imaging biomarkers of HD to measure effectiveness of treatments • Drugs in human clinical trials include Creatine, Coenzyme Q-10, omega-3 fatty acid Ethyl-EPA, Minocycline,
    43. 43. Striatal Input and Output 1 1
    44. 44. What is missing? – Effect of DA on pathways • Direct Pathway: Stimulates • Indirect Pathway: Inhibits • Overall Excitatory
    45. 45. DA in Direct Pathway Dopamine (+) Substantia Nigra pars compacta
    46. 46. DA in the Indirect Pathway Dopamine (-) Substantia Nigra pars compacta
    47. 47. How do I keep this all straight? • Basal Ganglia (Caudate, Putamen, and GP) – Medium Spiny neurons = GABAergic • GABA = Inhibitory • Cortex, Thalamus, STN – Here, looking at Glutamatergic neurons – Glut=excitatory • Dopamine from Substantia Nigra pc – Acts on Putamen
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