LETHIHUNG(202150450) huntingtons disease (1)

Huntington disease

LE THI HUNG, JEONBUK NATIONAL UNIVERSITY

Biometris
Quantitative Methods brought to Life


Outline
I . Huntington disease

II . Pathogenesis

III. Symptoms

IV . Diagnosis

V . Treatment

VI . Emerging therapies
Biometris
Quantitative Methods brought to Life

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I. Huntington disease




Definition: an autosomal dominant, neurodegenerative condition
Causes: pathogenic repeat expansion of CAG trinucleotide in exon 1 of the hunting gene (HTT) on chromosome 4

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I. Huntington disease

The average age at diagnosis

Meta-analyses show a worldwide prevalence of 2.7 per
100,000 with the highest

is

rates in Western

49 years old
populations and lowest among Asians

Both male and female, have a 50%

risk of inheriting the
faulty gene

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II. Pathogenesis

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III. Symptoms

Table 2. Motor symptoms of HD

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III. Symptoms

Table 3. Motor symptoms of HD

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III. Symptoms

 Cognitive symptoms:


Memory deficits



Psychomotor slowing



Impairment in executive, perceptual and spatial skills



The ability to communicate diminishes



Common speech difficulties include dysarthria, with poor articulation and slurring of words, slow production of words,

poor speech initiation and difficulty organising thoughts

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III. Symptoms

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III. Symptoms

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III. Symptoms

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III. Symptoms

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IV. Diagnosis



CAG repeats ≥ 40 to determine a positive test



Diagnostic testing can determine the nature of clinical presentation and guide treatment decisions

MRI brain comparison
and measurements in
control person and
Person with
Huntington’s Disease



Predictive testing those at risk for HD, usually a family history

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V. Treatment



There are no treatment to stop or reverse Huntington’s disease.



However, some medications can help keep symptoms under control:

-

Tetrabenazine

-

Antipsychotic drugs

-

Antidepressants

-

Tranquilizers



Better to do exercise.

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[REF: Tasuku Matsuoka and Masakazu Yashiro, 2018]

VI. Emerging therapies

HTT lowering

HTT modulation

Immunomodulation
Immunomodulation

Cell replacement

Deep
Deep brain
brain stimulation
stimulation

Synaptic modulation

Other medical therapies

<Scheme of HD emerging therapies>

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VI. Emerging therapies

1.

HTT lowering

-RNA- based approaches
-- One of the most intriguing and promising emerging therapy.
-- Only the use of ASOs has reached clinical stages of development.
-DNA- based approaches:
-- ZFPs were able to reduce mHTT levels and an HD-like behavioral phenotype. These models has high CAPrepeat numbers (115-160 repeats). (no clinical studies of ZFPs in HD).

-- CRISPR – Cas9: reduce DNA breaks at sequence- specific sites.

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VI. Emerging therapies

2. HTT modulation

 Selisistat
- A SirT1 (silent information regulator T1) inhibitor.
-

A selective decrease of mHTT levels (Drosophia and mouse models)  may specially increase the rate of
clearance of mHTT.



PBT2:

-

An 8-hydroxyquinolin.

-

PBT2 treatment in an HD nematode and mouse model improved motor ability and ameliorated the toxic
effects of polyglutamine aggregation.

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VI. Emerging therapies

3.

Immunomodulation

-Laquinimod
-- An immunomodulatory drug originally studied for the treatment of relapsing-remitting multiple sclerosis.
--

A significant reduction of caudate atrophy and whole brain atrophy that was most evident in early HD.

-Semaphorin 4AD (SEMA4D):
-- A transmembrane signaling protein that modulates pathways of neuroinflammation.
-- The blockage of SEMA4D using a monoclonal antibody (mAb67-2)  reduced striatal, corpus, callosal and
cortical atrophy, improved behavioral measures (in an HD mouse model study).

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VI. Emerging therapies
4. Synaptic modulation



Pridopidine

- Have low D2 affinity and much higher affinity for the sigma-1 receptor (SIG1R)
- SIG1R agonist (PRE084) used in neuronal cells expressing mHTT  improved survival.



Phosphodiesterase 10A inhibitors

- A member of the PDE enzyme family to hydrolyze cAMP, cGMP  vital for modulating cyclic signaling
pathways  impairment of several transcription factors including the cAMP response element-binding protein
(CREB)



BN82451

Reduce neuronal death, improve mitochondrial dysfunction and reduce neuroinflammation

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VI. Emerging therapies
5. Other medical therapies



SRX246

- SRX246 is a novel vasopressin 1a (V1a) receptor antagonist being evaluated for the treatment of specific mood
disorders



Cysteamine

-Transglutaminase (TGA) inhibitor TGA promotes aggregation by crosslinking the expanded polyglutamine tract of
mHTT

6. Deep brain stimulation

-

Significant reduction of chorea

7. Cell replacement therapy

-

Replace lost cellsreversing disease or modifying progression
Replace the degenerated striatal MSNs and reconstruct neural circuity
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Key references

•

[1] Hassaan (2019). Emerging therapies in Huntington’s disease, Expert Review of Neurotherapeurics, Vol 19(10), 983-995 .

•

[2] Pierre, Samentha, Mark et.al (2018). Huntington’s disease: Neuropsychiatric manifestations of Huntington’s disease,
Australasian Psychiatry, Vol 26(1), 366-375.

•

[3] Anthony J. Hannan (2018. Synaptopathy, circuitopathy and the computational biology of Huntington’s disease, BMC biology, 16,
71-73.

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Thank you very much!