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Spinocerebellar Ataxia Type 3 / SCA Type 3 / AMT-150

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  1. flosz 19 november 2018 18:52

    • flosz

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    Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1; see this term), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations.

    Epidemiology
    Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence in North America, Australia and India. Accurate estimates of prevalence are not available. However, SCA3 is the most common form of ADCA1 in most genetically characterized populations and accounts for up to 72 % of families with ataxia. Based on an English language literature review about 600 cases have been published.

    Clinical description
    SCA3 is divided into 3 forms. SCA3 type 1 (MJD Type 1, see this term) is associated with ataxia, ophthalmoparesis, pyramidal signs such as spasticity and hyperreflexia, and extrapyramidal signs including dystonia and other movement disorders presenting in adolescence. SCA3 type 2 (MJD Type 2, see this term) presents in middle adulthood with ataxia, spasticity, and dystonia. SCA3 type 3 (MJD Type 3, see this term) occurs after the age of 40 and includes ophthalmoparesis and anterior horn cell disease, i.e. fasciculations, atrophy, and weakness. Parkinsonism can also be a feature of SCA3. A likely overlooked but common feature is impairment of temperature sensation involving the entire body.

    Etiology
    The disease is associated with a CAG repeat expansion mutation in the ATXN3 gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56.

    Diagnostic methods
    Diagnosis is based on the clinical picture, familial history and ultimately on genetic testing.

    Differential diagnosis
    Differential diagnosis is broad and includes other types of SCA which may have similar features.

    Antenatal diagnosis
    Prenatal diagnosis and pre-manifestation diagnosis in patients with a family history of SCA can be offered.

    Genetic counseling
    SCA3 follows an autosomal dominant pattern of inheritance with full penetrance and anticipation phenomenon. Genetic counseling is recommended in symptomatic patients or those with a family history of the disorder due to known SCA mutation, and pre-symptomatic testing should be discussed in adults.

    Management and treatment
    In the absence of specific treatments to slow or stop disease progression, care is supportive. For example, parkinsonism, restless legs syndrome, spasticity, sleep disorders and depression can be treated pharmacologically. Dystonia and spasticity can be managed with local botulinum toxin injections. Occupational and physical therapy are essential. Speech therapy may also be of benefit for managing dysarthria.

    Prognosis
    Prognosis is poor but patients have been reported to survive for decades after onset of symptoms.

    www.orpha.net/consor/cgi-bin/OC_Exp.p...

    Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model
    www.ncbi.nlm.nih.gov/pmc/articles/PMC...
    twitter.com/prof_dollar/status/104566...

    SCA3 vanaf pag.96: uniqure.com/R&D%20Day%20Full%20Sl...
  2. flosz 21 november 2018 14:25

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    $QURE new gene therapy candidate AMT-150, a novel treatment for Spinocerebellar Ataxia Type 3, a central nervous system disorder.

    Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the protein ataxin-3. People with SCA3 experience brain degeneration that results in movement disorders, rigidity, muscular atrophy and paralysis. There is currently no treatment available that slows the progressive course of this lethal disease.

    AMT-150 is a one-time, intrathecally-administered, AAV gene therapy incorporating the Company’s proprietary miQURE™ silencing technology that is designed to halt ataxia in early manifest SCA3 patients.

    In an in-vitro study with human Induced Pluripotent Stem (IPS) derived neurons, AMT-150 has been shown to lower the human ataxin-3 protein by 65 percent, without any off-target effects. The Company also performed a proof-of-concept in-life study in SCA3 mice demonstrating that AMT-150 was able to lower toxic ataxin-3 protein by 65 percent in the brain stem after a single administration.  Further studies in non-human primates demonstrate the ability to distribute and express a reporter gene at a clinically relevant level in the most degenerated brain regions in SCA3.

    These preclinical studies show that a single administration of AMT-150 results in sustained expression and efficient processing with on-target engagement.  They also show that AMT-150 appears to be safe due to the lack of off-target activity. The Company is currently performing studies in large animals to demonstrate further safety and efficacy.
  4. Prof. Dollar 23 februari 2019 12:26

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    quote:

    Yvonne schreef op 23 februari 2019 11:13:

    What is new according AMT-150? I have sca-03 and I am curious when treatment is possible.
    Hi Yvonne!

    Please contact Daniel Leonard. He is the Director of Global Patient Advocacy at uniQure. You can contact him via Patients@uniQure.com

    Furthermore, try to follow the news regarding AMT-130 for Huntington’s Disease (HD). AMT-130 uses the Company’s proprietary uniQURE™ silencing technology that will also be used in AMT-150. The company expects that this year AMT-130 will be the first one-time administered AAV gene therapy to enter clinical testing for the treatment of Huntington’s disease.

    Best,
    Prof. Dollar
    twitter.com/Prof_Dollar
  5. [verwijderd] 23 februari 2019 13:15

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    quote:

    Prof. Dollar schreef op 23 februari 2019 12:26:

    [...]
    Hi Yvonne!

    Please contact Daniel Leonard. He is the Director of Global Patient Advocacy at uniQure. You can contact him via Patients@uniQure.com

    Furthermore, try to follow the news regarding AMT-130 for Huntington’s Disease (HD). AMT-130 uses the Company’s proprietary uniQURE™ silencing technology that will also be used in AMT-150. The company expects that this year AMT-130 will be the first one-time administered AAV gene therapy to enter clinical testing for the treatment of Huntington’s disease.

    Best,
    Prof. Dollar
    twitter.com/Prof_Dollar
    Hi Prof. Dollar,

    Thank you for your quick respons. :-D

    Greetings from Holland.
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