huntington's disease, potential therapies
DESCRIPTION
Treatment options for Huntingtons Disease, Potential Targets.TRANSCRIPT
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 halt the progression of the disease !
• To reverse the neurodegenerative process !!!
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 !!!
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 (Focus of our journey)– Regulation of upper motor neurons– Necessary for normal initiation
Pathways of Motor Loop
• Direct Pathway– Overall Excitatory
• Indirect Pathway– Overall Inhibitory
Direct Pathway(aka the Express Route)
CORTEX
PUTAMEN
(GPe) (STN)
GP interna
VA/VL THALAMUS
Glutamate (+)
Glutamate (+)GABA (-)
GABA (-)
Indirect Pathway (aka, scenic route)
CORTEX
PUTAMEN
GP externa
STN
GP interna
VA/VL THALAMUS
Glutamate (+)
GABA (-)
Glutamate (+) GABA (-)
GABA (-)
Glutamate (+)
Huntington’s Disease
CORTEX
PUTAMEN
GP externa
STN
GP interna
VA/VL THALAMUS
Glutamate (+)
GABA (-)
Glutamate (+) GABA (-)
GABA (-)
Glutamate (+)
+
Symptom Drug Considerations
Chorea 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)
Voluntary motor impairment
Hypokinetic-rigid 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
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 !!!
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 !!!
Behavioural symptoms
Depression Tricyclic antidepressants
Agents with few anticholinergic adverse effects are preferred (e.g. desipramine†). Response is likely to be incomplete because of dose-limiting adverse reactions
SSRIs Anorectic adverse effects might theoretically accelerate bodyweight loss
Monoamine oxidase inhibitors
Frequent adverse effects. These drugs might worsen chorea via their effect on increasing brain dopamine levels
Anxiety Benzodiazepines -
Amitriptyline Possibly beneficial in depression-related anxiety
Irritability, aggression
Benzodiazepines -
Antipsychotics Especially those with sedative effects (e.g. haloperidol)
Propranolol, pindolol†
Paradoxical aggravation of aggression has occasionally been reported in patients with Huntington's disease
Psychosis Classical antipsychotics
Depot preparations might be helpful in noncompliant patients
Clozapine Useful for treatment-resistant psychosis and patients with marked hypokinetic symptoms
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 !!!
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 !!!
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.
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 !!!
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 !!!
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 Publishing Group
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
• “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.”
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, placebo-controlled 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.
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.
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 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
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 !!!
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 !!!
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 ventricleCC : corpus callosumDG : dentate gyrusCA1 :hippocampal CA1 pyramidal cells3V : third VentricleSCF : stem cell factorSSRI : serotoninselective reuptake inhibitor
Summary…..
Huntingtin-interacting Proteins
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.
Animal models
Destruction of striatal spiny neuronsSparing interneurons containing:SomatostatinNeuropeptid YNADPH-diapohrase/NO synthase positive neurons
Tools: Excitotoxin Quinolinic acid
Transgenic animals
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.
• Psychiatric disturbances such as depression, aggression, OCD, psychotic symptoms respond well to psychotropic drugs (SSRIs Prozac, Paxil, Celexa) or anti-epileptic medications (Valproic acid).
Research: Huntington Study Group (HSG)
At-Risk & Observational Research Studies-Repository 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
Experimental Clinical Compounds Transgenic Mouse Models of HD allow scientists to study
processes that cause neurons to die in HD, and assess drug therapies that may slow disease progression
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, Phenylbutyrate, Riluzole which have shown potential neuroprotective benefits in mouse models
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1
Striatal Input and Output
What is missing?
–Effect of DA on pathways
•Direct Pathway: Stimulates
•Indirect Pathway: Inhibits
•Overall Excitatory
DA in Direct Pathway
Substantia Nigra pars compacta
Dopamine (+)
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 = Inhibitory
• Cortex, Thalamus, STN– Here, looking at Glutamatergic neurons– Glut=excitatory
• Dopamine from Substantia Nigra pc– Acts on Putamen