The document discusses therapy for Huntington's disease. The main goals of therapy are to treat motor manifestations like chorea, treat psychiatric manifestations like depression and psychosis, provide supportive therapy, halt disease progression, and potentially reverse neurodegeneration. Medications are used to treat symptoms, while research focuses on disease-modifying therapies like creatine supplementation, HDAC inhibitors that alter gene expression, neural transplants, and stem cell therapies. Ongoing clinical trials evaluate compounds that could slow functional decline by targeting pathways involved in Huntington's pathology.

2. Therapy for Huntington’s
Disease
Dr. Rahul Kumar,
Senior Resident, Department of Neurology,
M S R Medical College

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. 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 !!!

5. Huntington’s Disease

6. Anatomy of the Basal Ganglia

7. 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

8. Pathways of Motor Loop
• Direct Pathway
– Overall Excitatory
• Indirect Pathway
– Overall Inhibitory

9. Direct Pathway
(aka the Express Route)
CORTEX
Glutamate (+)
PUTAMEN
Glutamate (+)
GABA (-)
(GPe)
(STN)
GP interna
GABA (-)
VA/VL THALAMUS

10. Indirect Pathway
(aka, scenic route)
CORTEX
Glutamate (+)
PUTAMEN
GABA (-)
GP externa
Glutamate (+)
GABA (-)
STN
Glutamate (+)
GP interna
GABA (-)
VA/VL THALAMUS

11. Huntington’s Disease
CORTEX
Glutamate (+)
PUTAMEN
GABA (-)
GP externa
Glutamate (+)
GABA (-)
STN
Glutamate (+)
GP interna
GABA (-)
VA/VL THALAMUS
+

12. 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)

13. 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

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. 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 !!!

16. 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

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. 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 !!!

19. 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.

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. 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 !!!

23. Downstream targets for therapeutics
for Huntington’s disease

26. Sweet Relief for Huntington
Disease
Masahisa Katsuno; Hiroaki Adachi;
Gen SobueNat Med 10(2):123-124, 2004.
© 2004 Nature Publishing Group

28. 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

30. • “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.”

31. 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.

32. 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.

33. Energy Depleting Enzyme May Be
Target for Huntington's Drugs
Chem Biol 2006;13:1-6

34. • 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

35. 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 !!!

36. 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 !!!

37. Neuron Transplant Stabilizes
Huntington's Disease for Several
Years
The Lancet Neurology on February
27, 2007

38. • "Neuroprotection could stop the disease," they
conclude, "but only a graft can restore lost
function."

39. Stem and progenitor cells of
the adult human nervous
system

40. Isolation and purification of neural progenitor cells

41. 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

42. Summary…..

45. Huntingtin-interacting Proteins

47. 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.

48. 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

49. 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.

50. 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

51. 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,

52. Striatal Input and
Output
1
1

53. What is missing?
– Effect of DA on pathways
• Direct Pathway: Stimulates
• Indirect Pathway: Inhibits
• Overall Excitatory

54. DA in Direct Pathway
Dopamine (+)
Substantia Nigra
pars compacta

55. DA in the Indirect Pathway
Dopamine (-)
Substantia Nigra
pars compacta

56. 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