Huntington’s Disease - PowerPoint Presentation

Slide1

Huntington’s Disease

Josiah McFarland,

Mattina

Girardot

, Elaine PlattSlide2
Huntington’s Disease Treatments and Therapies

No treatments, medications, or therapies can cure HD or alter the course of the disease

The disease cannot be stopped or slowed down at this point, only maintained

Drugs and effective therapies have been utilized to lessen the symptoms of movement and psychiatric disorders

C

ompelling

need to discover new treatments for motor disability in HD, particularly for non-

choreic

motor symptoms.Slide3
Current Treatments

Drugs

Specialists

Physical Therapists

Neurologists

Psychiatrists

Medical Geneticists TherapiesPhysical TherapySpeech TherapyCounselingSlide4
Treatments in the Making

Fruit Fly Models

Mouse Models

Gene Silencing

RNA Interference

Stem Cell Slide5
Medications for Movement Disorders

Tetrabenazine

(

Xenazine

)

– most common and first drug approved by the FDA to treat a Huntington’s Disease symptom

Levetiracetam (Keppra) and Clonazepam - very similar drugs mainly used to treat epilepsy but also are effective in reducing the chorea associated with HDAntipsychotic Drugs – have side effects of suppressing movement

Haloperidol (Haldol)ChlorpromazineSlide6

Tetrabenazine Suppresses involuntary jerking and writhing movements associated with chorea

Does not treat any other symptoms caused by HD

Reduces the amount of certain chemicals in the brain that help control body movement

Considered a dopamine

depletor

Inhibits the vesicular monoamine transporter 2 (VMAT 2). VMAT 2 is responsible for regulating how much of a neurotransmitter is released across the synapse in a neuron. Tetrabenazine prevents these neurotransmitters from binding to the receptors. Slide7

Tetrabenazine Clinical Trial Trial Design: Randomized, double-blind, placebo-controlled study over a 12 week period with 84 HD patients

Sponsor

: Ovation Pharmaceuticals

Results

:

Tetrabenazine reduced chorea symptoms in more than two thirds of patients. Patients who received the medication were six times likely to be considered improved by their doctors.Side Effects: sleepiness, depression, anxiety, agitation, and nausea. One suicide occurred during the study. Slide8

LevetiracetamClinical trial was held to evaluate the preliminary efficacy of

levetiracetam

in reducing chorea in HD patients

Primary endpoint measure was the Unified Huntington’s Disease Rating Scale (UHDRS) chorea sub score

Mean UHDRS chorea scores decreased from 12.6 +/- 3.0 at baseline to 6.7 +/- at endpoint

Results concluded that levetiracetam may be efficacious in reducing chorea in HD patientsSlide9
Haloperidol

Treating schizophrenia and acute psychosis, even the outbursts involved with Tourette’s Syndrome

Has some effect of the psychological disorders of HD

Think more clearly, have less anxiety, and take part in everyday life.

Primarily used for treatment of chorea.

Depends on the patient. Some see in increase in involuntary movements, while occasionally there is a side effect of suppressing movement. Slide10
Medications for Psychiatric Disorders

Antidepressants

– may also help treat the obsessive compulsive disorder found in some patients

Celexa

Zoloft

Prozac

Antipsychotic Drugs – may suppress violent outbursts, agitation, and other symptoms of mood disorders.SeroquelRisperdalZyprexia

Mood-Stabilizing Drugs – help prevent the highs and lows associated with bipolar disorderDepacon

EpitolSlide11
Effects of Medications

Drugs that treat some symptoms may result in side effects that worsen other symptoms

Each designated drug may effect a patient in a different way then the other, so not every medication is beneficial to a patient

Over time, drug tolerance may reduce subject’s reaction to a medication

Medication management is necessary over the course of the disease

Monitoring

of medications that a patient takes to confirm that he or she is complying with a medication regimen, while also ensuring the patient is avoiding potentially dangerous drug interactions and other complications.Slide12
HTT Protein

The abnormal protein (HTT) found in Huntington’s Disease leads to an unusually large amount of nerve signaling early in the disease process

Partially blocking these nerve signals prevents neuron death and loss of motor function in fruit fly models of HD

Findings suggest possible new ways of delaying the onset or progression of Huntington’s Disease

The HTT gene is located on the short (p) arm of

chromosome 4Slide13
Fruit Fly Models

Fly models with the full-length abnormal HTT protein showed a progressive loss of neurons and had shorter lifespans

HTT protein triggered a high transmission of nerve signals between neurons

Flies were developed with the HTT protein and a partial loss of the calcium channel genes or other genes needed for normal synaptic function

Absence of channels reduced synaptic function which counterbalanced the excessive amount of nerve signals caused by the abnormal HTT protein

As a result, the flies did not develop neuron loss or movement problemsSlide14
Fruit Fly to Human

Reducing the abnormal nerve signal activity in people with the HTT gene mutation might delay the onset of HD or slow the progression

Drugs that reduce nerve signaling are now being put into trial

Although Fruit Fly models may correlate to human patients affected with HD, this method is unlikely to cure Huntington’s DiseaseSlide15
Specialists involved in HD care

Physical TherapistsSpeech Language Pathologists

Neurologists

Psychiatrists

Primary Care Providers

Medical

GeneticistsGoals of these specialists: slow the symptoms and help the person function for as long as possible.Slide16
Physical Therapy

Treatment of physical disease, injury or disability

Therapeutic Exercises

Functional Training

Massage

Hydrotherapy

Heat TreatmentGoal: Maintain and support quality of lifeSlide17
HD’s side of Physical Therapy

Similar to Parkinson’s Disease, Muscular Dystrophy, Ataxia, Atypical Parkinson’s Disease, Tourette’s/Tics, and Dystonia

HD Symptoms: progressive

movement disorders, cognitive deficits, and behavioral

changes (all affect daily living)

Goals:

Enhance fitness, wellness and strength Maintain respiratory capacity Prescribe and fit assistive devices Stabilize gait and balance Educate and support caregivers (home exercise programs)Slide18
Stages of PT

Early Stage

Improve fitness

Strengthening

Balance

Gait

Core stability – Maintain respiratory system! – Posture Exercise program Home program Gym program Less time, more frequency limit fatigueMid Stage Keep mobile

Maintain function & quality of life Promote relaxation strategies Safety with ambulation Reinforce awareness

Functional training Transfers Caregiver training EquipmentLate Stage

Protect the patient

Promote Comfort

Prevent falls

Alter the patient’s environment

Establish a routine

Caregiver support

Respite CareSlide19
Results

Main issues found:Insufficient

use of routine physical therapy–related outcome measures at different stages of

HD

U

nderutilization

of physical therapy services in managing HD (particularly in the early stagesthe management of falls and mobility deficit progression is a key treatment aim for people with HD.Little data out there about physical therapy approaches to HD.Slide20
Speech Pathology

In later stages, used to preserve independence in communication and swallowing.

May involve alternate communication devices and techniques

Includes educating family and friends about communication techniques

Goal: Develop strategies for compensating for the communication, swallowing and cognitive issues that arise from the diseaseSlide21

Counseling

Physical therapy and speech therapy can help with depression

High rate of depression and suicide in HD patients

Includes talk

therapy to help

address

behavioral problemscoping strategiesexpectations of disease progressioneffective communication among family members.

Goal: balance the mental struggle of Huntington’s DiseaseSlide22

Non-Traditional Therapies

Technology

Gaming systems

Memory games

Visual Tracking

MusicArtSlide23

Mouse models for HD

Mice and humans have the Huntington gene

Mice version is 81% similar to humans but contains less CAG repeats

Three main kinds: knockout, transgenic, and knock inSlide24
Knockout model

Gene coding for Huntington has been removed so DNA is not transcribedSince no Huntington gene is present, the organisms die during embryogenesis

Indicated HD is a “gain of function” diseaseSlide25

Transgenic model

Human Huntington gene is inserted into nuclei of model organism

Location of gene insertion is not controlled

Results in both of the mouse’s copies and the mutated human copy to be expressed

Since mutated human gene is not regulated by mouse gene, overexpression of Huntington protein

Leads to more obvious disease phenotype.Slide26

Knock-in modelWhole or part of mutated human HD gene replaces the entire mouse Huntington gene.

Most true model

HD gene is in appropriate location and is regulated by promoter.

Allows for homozygous and heterozygous modelsSlide27
HD gene

Caused by a mutation on chromosome 4Often only on one allele (heterozygous).

Results in a larger version of the

htt

protein causing clumping.Slide28
Silencing genes

Two methods: ASOs and

RNAiSlide29
Slide30

RNAi (RNA interference)The goal is to destroy the mRNA coding for the mutated HTT

Long, double stranded RNA is identified by dicer

Dicer cuts up the

dsRNA

, and RISC picks up the

snipets (siRNA).RISC then splits RNA into single strands and finds matching mRNASlicer, another protein, then cuts up the mRNATranslation is preventedResearches can create siRNA

to match and turn off a specific gene.Slide31
C

hallengesD

elivery of

siRNA

into the brain

Viral vector

Spinal fluid (blood brain barrier)Injection directly into the brain DistributionsiRNA do not spread naturallyDifferent molecules (ASOS) may spread easierSide affects

Possible interference with other genes or moleculesSlide32
ASOs (antisense oligonucleotides)

Similar to RNAi

Small, single stranded DNA that binds to mRNA and disrupts translation

Spread better throughout the brain and last longerSlide33

Ionis pharmaceuticals 3 countries (UK, Germany, and Canada )

36 HD patients

Began phase 1 clinical trial using ASOs in October.

Use a lumbar puncture to deliver the ASO.

So far Phase 1 has been successful.Slide34
Stem cells as a model

Studying and understanding the disease

Patient cell

iPS

cell MSN

MSN can then be used for drug discoveries,

Or as a model to better understand the HD Slide35
Stem cells as a treatment

Replacing lost MSNs and restoring function.

Applies to other neurodegenerative diseases as wellSlide36
Next steps in stem cell therapy

Further information needs to be gathered on:Survival of lab-produced MSNs

Their similarity to those in our brain

Ability of these MSNs to integrate into the damaged brain

Long-term safety Slide37
Eradication of the Disease?

Genetic Testing options are now available to determine whether a child of a diseased patient has the mutated gene.

Since the onset of HD is not until later in life, many people have children without knowing they have the disease

There is a possibility of all affected people receiving test results and not having children based on the outcome. This would make passing on the disease impossible. Slide38
References

Busse, Monica E et al "Physical Therapy Intervention for People With

Huntington

Disease." 

Physical Therapy

 88.7 (2008): 820-831. Web.06 April.

2016.DeFranco, Meredith. "Physical Therapy in Huntington's Disease."Huntington's Disease Society of America. N.p.,

n.d. Web. 3 Apr. 2016."Huntington's Disease." American Speech-Language-Hearing Association. N.p

., 2016. Web. 06 Apr. 2016.Kantor, Daniel. "Huntington Disease." 

Medline Plus

. U.S. National Library of

Medicine

, 1 June 2015. Web. 3 Apr. 2016.Slide39

ReferencesZesiewicz

TA, Sullivan KL, Hauser, RA,

Sanches

-Ramos J. 2006. “

Open-label

pilot study of levetiracetam (Keppra) for the treatment of chorea in Huntington's disease.” National Center for Biotechnology Information. 21:11.

Romero E, Cha G-H, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas

J.  "Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm." 

Neuron

, January 10, 2008, Volume 57, Issue 1, pp. 27-40