uniQure - gene therapy SCA3 mousemodel

uniQure is a leading gene therapy company advancing transformative therapies for patients with severe medical needs.

Spinocerebellar Ataxia Type 3, 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 toxic protein ataxin-3, leading to brain degeneration that results in movement disorders, rigidity, muscular atrophy and paralysis.

The company has engineered an artificial microRNA candidate, AMT-150, to target the ataxin-3 gene in a SCA3 knock-in mouse model. 

An inactivated virus vector is used to deliver AMT-150 to the nerve cells. The virus containing AMT-150 is injected close to the cerebellum. 

The 6-week proof-of-concept study demonstrated that a single AMT-150 injection in the cerebrospinal fluid resulted in significant mutant ataxin-3 lowering at each of the primary sites of disease neuropathology, namely the cerebellum (up to 53%) and brainstem (up to 65%).

These results were corroborated by preclinical studies in human induced Pluripotent Stem Cell (iPSC)-derived neurons showing a dose-dependent lowering of ataxin-3 mRNA of up to 55%.

These studies further demonstrate the potential utility and safety profile of the miQURE™ technology, the Company’s proprietary gene-silencing platform.

“We believe that the data from these preclinical studies in the knock-in mouse model and in iPSC-derived neurons show the potential of AMT-150 to alter the course of this devastating disease after a single administration,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure.



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Press release, 7 May 2019

Ongeneeslijk zieke Soufiane (20) denkt niet aan toekomst: 'Ik wil leven. Nu.'

Soufiane heeft samen met verschillende Albert Heijn-vestigingen uit de buurt en zijn voormalige middelbare school De Rotonde geld opgehaald voor onderzoek naar SCA type 2. Alle jongens van de vriendengroep in de buurt hebben een gedrukt shirt gekocht, de opbrengst gaat naar het onderzoek. Omringd door zijn familie hoort hij het totaalbedrag: meer dan 22.700 euro.

Soufiane Elazizi (20) was net achttien toen hij aan de blik van zijn arts zag dat het mis was. Hij kreeg de diagnose SCA type 2, een ongeneeslijke ziekte waar zijn zus en vader al aan waren overleden. Soufiane weet dat hij niet oud zal worden, daarom heeft hij een bucketlist. "Bovenaan staat dat ik mijn moeder trots wil maken."

"Heel even, zo'n twee seconden, had ik echt geen idee waar ik was. Daarna zag ik het mooiste uitzicht dat ik ooit van mijn leven heb gezien", vertelt Soufiane, voor vrienden Souf. Twee weken geleden sprong hij uit het vliegtuig. Parachute springen staat op zijn bucketlist. Net als zijn diploma en rijbewijs halen, op bedevaart naar Mekka en met vrienden op vakantie.

Hier ga je aan dood

Die bucketlist heeft hij sinds zijn achttiende, nadat een arts hem vertelde dat hij de zeldzame ziekte SCA type 2 heeft. "De naarste variant, want hier ga je aan dood." Soufiane praat er nuchter over. Je ziet niet meteen dat hij ziek is. In het kantoor van supermarktmanager André geeft hij een stevige hand.

Soufiane moet zo werken in de Albert Heijn aan het Valkeniersplein in Breda. Hij heeft pretogen en een glimlach die lijkt te blijven plakken op zijn gezicht. "Ik blijf positief en leef met de dag. Ik ga er het beste van maken."

Mijn leven was een groot feest

SCA type 2 is een erfelijke aandoening van het centrale zenuwstelsel. Kort gezegd: Soufiane's kleine hersenen krimpen, waardoor de communicatie tussen zijn zenuwen en spieren steeds slechter wordt. Er zijn geen medicijnen voor, genezing is niet mogelijk.

"Mijn leven was een groot feest, maar dat is veranderd." Soufiane vertelt dat hij het liefst elke woensdag met vrienden gaat voetballen, af en toe een filmpje pakt en gaat stappen. Pas als hij praat, merk je dat er iets is. Het gaat wat langzamer.

Sinds een jaar merkt hij zelf steeds vaker dat hij ziek is. Lopen lijkt door evenwichtsproblemen meer op zwalken en zijn ogen bewegen trager. "Laatst hield een uitsmijter me tegen toen ik met vrienden een café in wilde. Hij dacht dat ik dronken was."

Niet iedereen gelooft het

Soufiane drinkt geen alcohol en legt op zo'n moment uit dat het zijn ziekte is. Niet iedereen gelooft het. Ook sommige klanten bij Albert Heijn niet. "Bij de zelfscankassa moest ik laatst vijf boodschappen controleren. 'Je hoeft niet zo te trillen hoor', zei een klant. Doe maar normaal."

Spierkrampen en trillingen zijn symptomen van de ziekte, hij kan er niks aan doen. Vergelijk het met een lichte vorm van epilepsie, alleen dan constant. "Ik ga geen stennis schoppen als mensen een opmerking maken, ik neem het ze niet kwalijk en loop gewoon weg. Als ze me beter kennen, zouden ze het begrijpen."

Ik heb urenlang gehuild toen ik het hoorde

De eerste klachten krijgt Soufiane twee jaar geleden, na een dag lossen en vakken vullen in de supermarkt. Zijn rugpijn gaat maar niet over. "Mijn huisarts vond dat ik me aanstelde, tot ik vertelde dat mijn vader en zus zijn overleden aan een zenuwaandoening. Hij verwees me meteen door naar het ziekenhuis."

Het is niet te zeggen hoe snel iemand met SCA type 2 overlijdt. Dat kan binnen een paar jaar zijn, maar het kan ook tien jaar duren. Soufiane's vader was 45 toen hij de diagnose kreeg en overleed vijf jaar later. Soufiane was toen acht. Zijn zus kreeg de diagnose bij haar geboorte en is zeven jaar geworden. Twee ooms overleden binnen vijf jaar na hun diagnose.

De bucketlist

"Zodra de arts vertelde dat mijn uitslag positief was, heb ik heel hard gehuild. Urenlang." Zijn broer zit naast hem in de kamer van de arts als hij de uitslag krijgt. "Hij is mijn vader, moeder en vriend ineen. We spraken elkaar moed in. Ik zei tegen hem dat ik de aankomende jaren eruit ga halen wat erin zit." Vandaar die bucketlist. Eén wens is al afgevinkt: een ondernemer uit Breda regelde de parachutesprong.

In augustus gaat hij met zijn broer en moeder mee naar Mekka. Die wens wordt afgevinkt. En die vakantie met vrienden gaat ook lukken. Maar zijn rijbewijs haalt hij waarschijnlijk niet. Door zijn ziekte komt hij niet door de medische keuring. "Ik was al afgekeurd voor ik überhaupt in een lesauto zat." Soufiane ziet zichzelf wel met een scootmobiel door de wijk scheuren, als lopen niet meer gaat. "De aanvraag voor een brommerrijbewijs loopt nog."

Mijn moeder doet alles voor me

Sinds een half jaar merkt hij dat hij weer achteruit gaat. "Dat voetballen hè, voor rennen heb je evenwicht nodig. En controle over de bal heb ik ook al niet meer. Ik hou het soms maar een kwartier vol. Ook tillen moet ik nu laten doen." Maar hij huilt er niet om. Dat doet hij sowieso weinig. Alleen hier, in het kantoor van André, als hij over zijn moeder praat, moet hij een tissue pakken. "Mijn moeder doet alles voor me. Ze zet mijn eten klaar als ik uit werk kom en wacht altijd tot ik thuis ben, ook al is dat pas laat. Ze laat nooit merken dat ze het zwaar heeft, ondanks dat ze haar man en kind heeft verloren."

Zijn moeder trots maken staat dan ook bovenaan de lijst. Daarom gaat hij nog steeds naar school, hij volgt een opleiding tot eerste verkoper. Het is een combinatie van werken en leren, het leerbedrijf is de Albert Heijn. "De meeste jongens van mijn leeftijd zien werken in de supermarkt als bijbaantje. Die maken zich druk om geld en dure kleding. Ik heb het hier naar mijn zin en weet dat gezondheid echt veel belangrijk is dan geld."

Ik maak van iedereen mijn vriend

Soufiane heeft een vast contract voor 20 uur, gekregen van André. Die noemt hij 'zijn werkvader'. Zijn moeder wil hij liever geen slecht nieuws brengen, dus praat hij met André over zijn ziekte, het verloop en wat hij moet doen om school te halen en daarnaast te werken. "Ik werk wat ik kan. Vandaag sta ik ingeroosterd voor vier uur."

Niet alleen in de supermarkt kent iedereen hem, Soufiane is inmiddels een bekende in de wijk het Ginneken. Hij is vaak in het zwembad te vinden, waar hij badmeester speelt. "Natuurlijk ben ik geen badmeester, maar iedereen kent me daar. Mensen komen naar me toe voor een praatje. En als iemand wordt lastiggevallen door een groep jongeren, spreek ik ze erop aan. Ik maak van iedereen mijn vriend."

Minder energie

Soufiane merkt dat mensen vaker naar hem luisteren, waarschijnlijk omdat hij ziek is. "Ik krijg weleens een grote bek als ik jongeren aanspreek op hun gedrag. Vorige week kreeg ik een berichtje: 'Sorry Souf, voor wat ik gedaan heb in het zwembad, ik zal het niet meer doen.' Zie je, ik maak van iedereen mijn vriend."

Het laatste half jaar heeft Soufiane minder energie. Hij is vaker moe. Zijn ogen vallen sneller dicht. Dat is 'goed balen'. "Maar je doet er niks aan." Over de toekomst wil hij het liever niet hebben. "Als mijn tijd is gekomen, dan is mijn tijd gekomen. Ik ben gelukkig met wat ik nu heb. Ik heb een perfecte jeugd gehad en ben omringd met mensen die van me houden. Meer kan ik toch niet wensen?"

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RTL nieuws, 30 juni 2019

Treatment with a dietary supplement for a rare ataxia: SCA38

Research presented at the International Ataxia Research Conference in September 2017 and published in a medical journal, highlights a treatment option for a very rare form of ataxia.

What causes SCA38?

A team at the University of Brescia in Italy found the gene causing SCA38 in three Italian families with late-onset, slowly progressive ataxia. Most of these patients also had nystagmus (involuntary eye movement), pes cavus (hollow foot sole) and a reduced sense of smell.

Following on from that discovery in 2014, the team studied the cellular mechanisms that cause the condition. The researchers found that SCA38 is caused by mutations in a gene called ELOVL5, which codes for an enzyme that makes polyunsaturated fatty acids, including one called docosahexaenoic acid (DHA). Usually, this enzyme is found in high levels, mostly in the cerebellum. In SCA38, however, the enzyme’s function is affected and might be harmful, as it reduces the levels of DHA.


This important discovery has led the team to carry out a treatment trial with 10 of their SCA38 patients, testing the effect of supplementing DHA (a dietary fatty acid supplement). The rationale for the trial is two-fold: firstly, to compensate for the reduction in DHA; secondly, because of the low level of DHA in SCA38, levels of the ELOVL5 enzyme are increased. This enzyme is the mutated, harmful version; therefore, increasing DHA levels should decrease the levels of the harmful ELOVL5 mutated protein.

Trial shows positive results 

A four-month, double-blind and placebo-controlled trial was performed in 10 people with SCA38 (five on treatment and five on placebo). This was followed by a 40-week period in which every participant took the DHA supplement. Results showed a statistically significant change in
the ataxia symptoms among the treatment group, as measured by the SARA ataxia rating scale (but not the ICARS rating scale), compared to the placebo group. The assessment made with the SARA and ICARS in the 40-week second phase also showed that there was a statistically significant difference between the scores at the start and at the end of the trial. The researchers also measured results by using a brain scanning technique, which reported a change in the cerebellum’s metabolism after the 40-week treatment, compared to baseline. There were no side effects reported.

Implications of the results 

Although the trial was very small, the lack of side effects and the fact that the treatment is an inexpensive dietary supplement which makes up for the insufficient natural levels, suggests that this could be a treatment option for neurologists to consider for SCA38 patients.


Lead researcher, neurologist Dr Barbara Borroni, told Ataxia UK: “All participants of the trial have chosen to continue taking the DHA supplementation after the trial ended and we are pleased with the continued improvement in their condition. At this stage we are not planning further trials but we would recommend any patients diagnosed with SCA38 to be treated with DHA under the supervision of their neurologist. Due to genetic screening being done in some hospitals in Italy, we are now aware of two further people having been diagnosed with SCA38 and treatment with DHA has been initiated.”

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Ataxia UK magazine, 203, autumn 2018

Using gene silencing to alleviate common ataxia

June 20, 2018


Michigan Medicine - University of Michigan

In what researchers are calling a game changer for future ataxia treatments, a new study showed the ability to turn down the disease progression of the most common dominantly inherited ataxia, Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease.

Spinocerebellar ataxia type 3 (SCA3) affects about one in 20,000 people. There's no disease-modifying therapy available, and patients slowly progress to an early death. A single gene mutation causes this neurodegenerative disease, making it an ideal target for a group of University of Michigan researchers.


For this preclinical study published in the Annals of Neurology, University of Michigan researchers employed nucleotide-based gene silencing to target the SCA3 disease gene, ATXN3. They greatly reduced levels of the mutant RNA coded by the gene in a mouse model of the disease without any toxic effects.


"Recent advances in antisense oligonucleotide technology provided us with a great opportunity for therapeutic targeting ," says co-first author Hayley McLoughlin, Ph.D., research investigator in the U-M Department of Neurology. "Although we still don't yet know the exact point of no return for this disease, we know how to turn things down before the disease burden accumulates to the point of detriment."

After two treatments, McLoughlin says the mouse model, which normally replicates similar disease motor phenotypes, is completely rescued. Importantly, it's the first time this animal model has been corrected through any therapy and is substantial proof-of-concept for future human clinical trial preparation.


"These encouraging results move us one step closer to disease-slowing therapy for this fatal disorder," says senior author Henry Paulson, M.D., Ph.D., a U-M professor of neurology and director of the Michigan Alzheimer's Disease Center. "They also offer hope that similar approaches might work for a number of brain diseases caused by the deleterious action of specific disease genes."

Team awarded $2.15M

Next, the U-M team in collaboration with Ionis Pharmaceuticals will pursue final drug development with a new U01 grant from the National Institute of Neurological Disorders and Stroke, at the National Institutes of Health. The U01 CREATE Bio Optimization Track funds researchers' work on potential therapies with an end goal of nominating a clinical candidate.


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Hayley S. McLoughlin, Lauren R. Moore, Ravi Chopra, Robert Komlo, Megan McKenzie, Kate G. Blumenstein, Hien Zhao, Holly B. Kordasiewicz, Vikram G. Shakkottai, Henry L. Paulson. Oligonucleotide therapy mitigates disease in Spinocerebellar Ataxia Type 3 mice. Annals of Neurology, 2018; DOI: 10.1002/ana.25264

Abnormal eyeblink in preclinical SCA3 mutation carriers

Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration.

To study the earliest stages of cerebellar dysfunction an eye blink test is performed in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls. The participants were presented with repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms.


Preclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset.

Eye blink is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. The eye blink test can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

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Artikel

IntraBio Receives Spinocerebellar Ataxia Orphan Drug Designation from the FDA

December 10, 2018


IntraBio Inc., a late-stage biopharmaceutical company developing novel therapies for rare ("orphan") and common neurodegenerative diseases, announced that the US Food and Drug Administration has granted Orphan Drug Designation (ODD) to its lead compound series (IB1000s) for the treatment of Spinocerebellar Ataxias (SCAs).


IntraBio has previously been granted Orphan Medicinal Drug Designation from the European Commission for IB1000s for the treatment of Spinocerebellar Ataxias.

"IntraBio's efforts to pursue a treatment for Ataxia is direly needed by the Ataxia patient population," National Ataxia Foundation’s (NAF) Medical Director, Susan Perlman, MD, said. "The Orphan Drug Designation of the IntraBio lead compound series (IB1000s) will accelerate development of this agent, which has potential symptomatic and neuroprotective activity for SCA and other Central Nervous System disorders. NAF supports IntraBio's efforts to offer the Ataxia community a treatment option that may alleviate some of their life-altering symptoms."

IntraBio has evaluated the effect of IB1000s in compassionate-use studies in over 175 patients, forming the scientific basis for IB1000s to be further investigated for the treatment of 18 indications, including hereditary ataxia.

IntraBio is currently in the process of applying for multi-national clinical trials with its lead asset (IB1001) for the treatment of certain inherited Cerebellar Ataxias.

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Press release

Spinocerebellai ataxia 48 (SCA48)

A new spinocerebellar ataxia (SCA48) is characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA.

STUB1gene

A family has been followed for more than a decade with periodic neurologic and neuropsychological examinations. Whole exome sequencing was performed in 3 affected and 1 unaffected family member.


Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with cerebellar atrophy. Three presymptomatic patients showed cerebellar atrophy cerebellum, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum.


This report describes a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. 

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UniQure - gene therapy pipeline extended to SCA3

November 19, 2018


Lexington (MA, USA) and Amsterdam (Netherlands)


uniQure N.V., a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced the expansion of its research pipeline with novel AAV gene therapy approaches to treating among others Spinocerebellar Ataxia Type 3 (SCA3) at the Company’s Research & Development Day held this morning in New York City.

“We are very proud of the progress the Company has made to deliver extensive preclinical data for these new gene therapy programs that expand our pipeline and further validate uniQure’s potential best-in-class vector delivery platform,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure. “The addition of these gene therapy candidates for indications in the liver and CNS brings us yet another step closer towards uniQure's goal of delivering transformational medicine to patients suffering from genetic diseases. We look forward to advancing these programs closer to the clinic in 2019.”

uniQURE introduced the new gene therapy candidate AMT-150 as a novel treatment for Spinocerebellar Ataxia Type 3 (SCA3), a central nervous system disorder.


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.
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Pressrelease

Spinocerebellar ataxia: imaging biomarkers

Currently, the most common clinical scores for rating the disease severity are the Scale for the
Assessment and Rating of Ataxia (SARA). However, the SARA score cannot be used to evaluate pre-manifest individuals and their small effect size would require large numbers of patients in clinical trials, which is an issue due to the scarcity of SCA.


As gene-based therapies are showing promise in preventing or reversing SCA pathophysiology, there is a need for biomarkers with effect sizes greater than clinical scores, which can be used in trials on small sample sizes.

Study

In the study a unique cohort of 57 patients with SCA1, SCA2, SCA3  and SCA7 and 24 healthy controls of similar age, sex and body mass index was enrolled. Longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months) were collected.

Clinical scores worsened as atrophy increased over time. However, atrophy of cerebellum and pons showed very large effect sizes compared to clinical scores. Imaging was sensitive to microstructural cross-sectional differences that were not captured by conventional methods. Automated imaging also showed larger effect sizes than manual imaging.

Conclusion

This study showed that volumetry (imaging) outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7.


Therefore, the researchers advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, automated imaging showed larger effect size than manual imaging to detect cross-sectional microstructural alterations in patients relative to controls.

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Autosomal dominant cerebellar ataxias: Imaging biomarkers with high effect sizes, Isaac M. Adanyeguh et al., Neuroimage Clin. 2018; 19: 858–867.
Published online 2018 Jun 14. doi: 10.1016/j.nicl.2018.06.011

Antisense oligonucleotides restore visual function in a mouse model of SCA7

Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder caused by mutations in the ATAXIN-7 gene. SCA7 is characterized by impairments in coordination, balance, and speech and by retinal degeneration. Retinal degeneration results eventually in complete blindness.


Niu et al. developed a strategy for treating visual impairments in SCA7 by inhibiting the mutated Ataxin-7 in the retina using antisense oligonucleotides (ASOs).


To explain how this technique works, I start with our genes. Our genes are made out of DNA, a chemical code that includes the information that allows our cells to function. This information is used to make proteins, the molecular machines and building blocks that are crucial for cells to work. Antisense oligonucleotides intervene at a critical intermediate stage between DNA and proteins – where the DNA is converted into a molecule called messenger RNA (or mRNA for short). mRNA is very similar to DNA, but much less stable, and chemically very slightly different. It acts as the template for making proteins. If you can get rid of it, the proteins don’t get made. Antisense oligonucleotides are synthetic fragments of DNA that can bind to mRNAs, causing them to be cut into pieces.

Intravitreal injection (injection in the eye) of ASOs specifically targeting the mutated Ataxin-7 reduced protein expression in the retina and ameliorated pathology and vision loss in a SCA7 mouse model.


The results suggest that ASOs targeting ATAXIN-7 might be effective in treating retinal degeneration in patients with SCA7.

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http://stm.sciencemag.org/content/10/465/eaap8677.short

Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD.

This study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings.


Thirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable.

Conclusions

Patients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.

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Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation, Sleep Med. 2018 Apr 25;48:23-26. doi: 10.1016/j.sleep.2018.04.002. [Epub ahead of print]

The 2018 Ross Prize in Molecular Medicine will be awarded to Dr. Huda Y. Zoghbi for her research unveiling the genetic and molecular basis of Rett syndrome and spinocerebellar ataxia, enabling novel therapeutic strategies for these devastating diseases. Complemented by fundamental studies in neurodevelopment, Dr. Zoghbi continues to pursue the complex molecular processes driving the pathogenesis of some of the most devastating neurological conditions.


The Ross Prize in Molecular Medicine was established in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine to recognize biomedical scientists whose discoveries transformed the way medicine is practiced. The awardees are midcareer researchers who have made a significant impact in the understanding of human disease pathogenesis and/or treatment. Moreover, it is anticipated that they will continue to make profound advances in the general field of molecular medicine.


On the exact same day in 1993, both Dr. Huda Zoghbi and Dr. Harry Orr independently discovered the mutation responsible for SCA1. But this wasn’t a simple genetic deletion or point mutation. Zoghbi and Orr found that the affected gene, ATXN1, has a repetitive CAG trinucleotide sequence, also known as a polyglutamine tract. They discovered that this region is prone to errors during DNA replication, resulting in expansion of the polyglutamine tract. Healthy patients have ~30 CAG repeats in ATXN1, while SCA1 patients have 40 or more. In families affected with SCA1, the number of CAG repeats increases with each generation, correlating with increased severity and an earlier age of disease onset.

Zoghbi’s lab also found that this altered ATXN1gene sequence encodes a bulky, improperly folded protein that is toxic to brain cells. These studies are relevant to multiple neurodegenerative diseases, including Alzheimer’s disease, which also involves misfolded proteins and neurotoxicity.

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The New York Academy of Sciences

Cadent Therapeutics initiates phase 1 clinical study

On March 12, 2018, Cadent Therapeutics, a precision neuroscience company developing novel medicines to restore movement and cognitive function in patients with neurological and psychiatric disease, announced the initiation of a Phase 1 clinical study for its lead product candidate CAD-1883. The compound is a selective first-in-class positive allosteric modulator of the small conductance calcium-activated potassium (SK) channel.

“This is an important step in the development of meaningful new therapies for people with movement disorders,” said Michael Curtis, PhD, President and CEO of Cadent Therapeutics. “We have shown that allosteric modulation of the SK channel restores cadence to neuronal firing and is efficacious in disease models of ataxia and tremor. Our hope is that by precisely tuning dysregulated neuronal firing, we can reduce disability and restore motor function in patients with spinocerebellar ataxia and essential tremor.”

In patients with spinocerebellar ataxia and essential tremor, the firing pattern of neurons in the cerebellum has become dysregulated, resulting in the loss of motor control, impacting mobility and fine motor function. By changing the calcium sensitivity of SK channels, CAD-1883 causes potassium current to flow at lower calcium concentrations, restoring neuronal firing regularity and improving motor function.

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News release

Ionis closes strategic collaboration with Biogen to develop drugs for a broad range of neurological diseases

Excerpt from Press release June 5, 2018


Ionis Pharmaceuticals announced today that it closed its expanded strategic collaboration with Biogen to discover and develop novel antisense drugs for a broad range of neurological diseases.


On April 20, 2018, Ionis and Biogen announced they would expand their strategic collaboration to develop novel antisense drugs for a broad range of neurological diseases through a new ten-year collaboration. This collaboration capitalizes on Ionis' leadership in RNA-targeted therapies as well as Ionis and Biogen's joint expertise in neuroscience research and drug development. It builds upon a productive collaboration that produced SPINRAZA® (nusinersen), the first and only approved treatment for patients with spinal muscular atrophy.

The companies plan to advance programs for a broad range of neurological diseases for which few treatment options exist today. Disease areas include dementia, neuromuscular diseases, movement disorders, ophthalmology, diseases of the inner ear, and neuropsychiatry.

Ionis will be responsible for the identification of antisense drug candidates based on selected targets, while Biogen will have the option to license therapies arising out of this collaboration and will be responsible for and pay for non-clinical studies, clinical development, manufacturing, and commercialization. In addition, Biogen may pay milestone payments, license fees and royalties on net sales.

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Patients with cerebellar ataxia do not benefit from limb weights

Patients with cerebellar ataxia are sometimes treated by the addition of mass to the limbs, though this practice has received limited study. 

Recent work suggests that adding mass to the limbs might have predictable effects on the pattern of cerebellar dysmetria (i.e., over or undershooting) that depends on a hypothesized mismatch between the actual limb inertia and the brain's estimate of limb inertia. Based on this model, the researchers predicted that addition of mass would only be effective in reducing dysmetria in hypometric patients. 

Cerebellar patients were challenged with making a single-joint, single degree of freedom reaching movement while various limb masses were tested. In this task, some single-jointed reaches were improved by adding masses that were optimized in a patient-specific manner. However, this improvement did not translate to multi-joint movements. In multi-joint movements, the "best" patient-specific masses (as determined in a single-joint task) generally exacerbated subjects' reaching errors. 

This finding raises questions as to the merits of adding limb weights as a therapy to mitigate the effects of dysmetria.

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Patients with Cerebellar Ataxia Do Not Benefit from Limb Weights, Zimmet, A.M., Cowan, N.J. & Bastian, A.J. Cerebellum (2018). https://doi.org/10.1007/s12311-018-0962-1

READISCA is Recruiting for SCA Research

READISCA is recruiting for SCA research in 18 study sites across the US. SCA1 and SCA3 participants are needed!

READISCA is a study to get ready for treatment trials that are anticipated within the next 5 years. The study will aid in clinical trial readiness for SCA1 and SCA3. The study is not a treatment trial.

Who is asked to participate?

• Individuals with a  clinical or genetic diagnosis of spinocerebellar ataxia type 1 or type 3 (SCA1 or SCA3) 

or

• Individuals with a first-degree relative that has a diagnosis of SCA1 or SCA3.

Participants should be in early or pre-symptomatic stages of the disease.

Main goals of the study

• To establish the world’s largest group of early stage and symptomless SCA1 and SCA3 individuals.
• To validate imaging signs in early stage and symptomless SCA1 and SCA3 individuals.
• To adapt recent ndings to design clinical trials for spinocerebellar ataxias.

This research visit will likely take about half a day. Participants will be asked to return annually for the next five years

Research visit

We will draw blood and perform DNA testing to confirm the genetic diagnosis. If you wish to know your gene status, we will release the DNA results to your doctor or genetic counselor at no cost to you.
You will be asked about optional spinal fluid collection by spinal tap (you can say “no” but the spinal fluid is extremely important for developing new drugs for SCAs).


If qualified, you will be asked to participate in an imaging study using an MRI machine in Boston, Baltimore, Minneapolis or Gainesville (FL).


There will be no cost for participation, and all expenses will be paid.

A simplified method for generating Purkinje cells from human-induced pluripotent stem cells

The role of the cerebellum in the coordination of smooth movements is well established. More recently, multiple lines of evidence have implicated this critical brain region in perception, emotion and cognition, via its extensive connections with cortical and subcortical centers.


Impairment of the cerebellar circuitry has been linked to the development of numerous motor and non-motor diseases, including ataxia.


The cerebellum is an intricately ordered structure, containing more neurons than any other brain region. Central among these are the Purkinje cells.

Purkinje cells (red) 

Dissecting the molecular mechanisms underlying this vulnerability requires a suitable model for the study of cerebellar development and degeneration. In the case of humans, brain tissue from affected individuals is difficult to obtain and is typically acquired postmortem, offering only limited insights into an advanced stage of pathology. Mouse models, on the other hand, can be studied throughout development. Nevertheless, they are hampered by species-specific differences in brain structure and gene function, which may affect the interpretation of results.


A big breakthrough in the field of human neurodegenerative disease research to date has come in the form of induced pluripotent stem cells (iPSCs). These cells can be derived directly from patients carrying disease-causing mutations. Importantly, they also have the potential to differentiate into any cell type of the body, offering the unique opportunity to study human neurons in vitro without the need for invasive surgical techniques shedding light on the pathology of numerous neurodegenerative diseases, including several of the spinocerebellar ataxias.


However, studies of cerebellar neurons remain remarkably rare, largely due to the complexities of development and neuronal architecture.


The authors describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs, enabling investigations into disease mechanisms and therapeutic development using disease-relevant patient cells. Past approaches to differentiate cerebellar neurons from hiPSCs have proven lengthy, technically challenging and difficult to reproduce, and it is the author's hope that continued innovations, such as the simplified protocol described here, may make these models more accessible, in order to enable future advances in the field.

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Watson, L.M., Wong, M.M.K., Vowles, J. et al. Cerebellum (2018).
A Simplified Method for Generating Purkinje Cells from Human-Induced Pluripotent Stem Cells https://doi.org/10.1007/s12311-017-0913-2

Internationale ataxie conferentie 2017

INTERNATIONALE ATAXIE ONDERZOEKSCONFERENTIE 2017
27 - 30 september, Pisa, Italië



Elke twee jaar komen wetenschappers van over de hele wereld bijelkaar gedurende drie en een halve dag om met elkaar te spreken over de laatste ontwikkelingen in het onderzoek naar ataxie. Er waren niet alleen presentaties van onderzoekers die zich richten op ataxie maar ook presentaties van mensen buiten de ataxie wereld om nieuwe inzichten te geven.


Het congres werd bezocht door wetenschappers, artsen, regelgevers, geneesmiddelenindustrie, patiëntvertegenwoordigers en patiënten.

PREPARE

Op woensdagochtend voor dat het congres van start ging, kwam de ‘PREPARE’ groep bij elkaar. Ik was hierbij uitgenodigd als vertegenwoordiger van de Europese ataxie patiënten. PREPARE is een wereldwijd samenwerkingsproject. Het project bestudeert autosomaal recessieve ataxieën (ARCAs).


Bij recessieve ziektes is het gezonde gen de baas. Dus als jouw vader of moeder de fout op één versie van het gen heeft, is hij of zij niet ziek. Want het andere, gezonde gen is de baas. Zij hebben dus één versie van het gen met, en één versie zonder de fout. Maar je ouders kunnen de mutatie wel doorgeven. Ze zijn 'drager' van de aandoening. Pas als beide ouders allebei een fout (mutatie) op een bepaald gen doorgeven, erf je de ziekte. Dat is vaak onverwachts, omdat je ouders niet merken dat zij drager zijn. De kans dat ouders de fout allebei doorgeven, is altijd 25%. Er is ook 25% kans dat het kind de fout niet erft, en 50% kans dat het kind drager is.


Recessieve ataxieën (ARCAs) zijn nog zeldzamer dan dominante ataxieën. Door vernieuwde technieken worden steeds meer mutaties bekend die de ARCA’s veroorzaken. Het project richt een wereldwijde database op met patiënten en hun mutatie. Van een groep patiënten waarvan de mutatie nog niet bekend is zal het hele DNA in kaart gebracht worden om de mutatie op te sporen. Op deze manier kan het ziekteverloop van groepen patiënten gevolgd worden. Om meer inzicht te krijgen in de verschillende mutaties, zullen de mutaties in een fruitvlieg model geplaatst worden. Op deze manier hopen de onderzoekers een beeld te kunnen krijgen hoe de mutatie de ziekte veroorzaakt. Later zal er een model in een knaagdier ontwikkeld worden.

Moleculaire basis van de aandoening

Woensdagmiddag ging het congres van start met als thema ‘de moleculaire basis van de aandoening’. De presentaties gingen over het bestuderen van de structuur en functie van genen op een moleculair niveau. Met behulp van moleculaire biologie kunnen genetische mutaties beter begrepen worden.


Er waren presentaties:

· over het vinden van nieuwe gen mutaties
· over de rol van een mutatie op het functioneren van mitochondriën (energiefabriek in cellen)
· over de rol van een mutatie op het doorgeven van elektrische signalen over de wand van de cel
· over de afname van zenuwcelstructuren in de kleine hersenen (SCA1)

De dag werd afgesloten met een receptie in de tuin. Zo kregen we eindelijk de kans om na het drukke programma elkaar te spreken.

Translationele modellen van ataxie

Donderdagmiddag kwam het thema ’translationele modellen van de aandoening’ aan bod. Het gaat over het vertalen van fundamenteel wetenschappelijk onderzoek naar de praktijk of te wel van laboratorium tot bed.


Er waren presentaties:

· over SCA7 muismodel
· over meetbare indicatoren bij ataxieën met een verlengd stukje DNA
· over het opruimmechanisme in de cel bij SCA3
· over het dagelijks leven (kwaliteit, depressie, activiteiten) bij SCA1, SCA2, SCA3, SCA6

Patiëntenperspectief

Vrijdagochtend was er een ronde tafel discussie over het patiëntenperspectief. Hieraan was ik uitgenodigd om deel te nemen. Patiënten en zorgverleners werden bevraagd over de diagnose, symptomen, communicatie met familie, kwaliteit van leven, ervaring met klinisch onderzoek, en welke symptomen wij het belangrijkst vinden om te behandelen. Vooral dit laatste aspect is heel belangrijk en verrassend voor onderzoekers. Veel patiënten geven de voorkeur aan zo lang mogelijk duidelijk te kunnen spreken. Meeste onderzoekers richten zich juist op het (niet meer kunnen) lopen. Ook kwam duidelijk naar voren bij de Friedreich’s ataxie patiënten die deelgenomen hadden aan klinische studies dat zij gefrustreerd waren door het gebrek aan communicatie over de studie. Geen van de deelnemers kreeg te horen hoe de studie verlopen was.


Aan het einde van de sessie kregen we van verschillende wetenschappers te horen dat het panel het hoogtepunt van het congres was. Vele fundamentele onderzoekers hebben heel weinig contact met de patiënten. Voor hen is het heel leerzaam te horen hoe families met de aandoening omgaan.

Vrijdagmiddag waren er presentaties over het verloop van de aandoening en hoe de progressie van de aandoening te meten (biomarkers). Ook is er gesproken over de endpoints van een klinisch onderzoek. Endpoints zijn de eigenschappen die in een klinisch onderzoek gemeten worden (loopafstand, functie hand, oogbewegingen, ….). Endpoints zijn ongelofelijk belangrijk bij het opzetten van een onderzoek. De endpoints bepalen of een onderzoek is geslaagd of niet.


De dag werd afgesloten met een diner in ‘Arsenali Repubblicani’ een werf uit de 13e eeuw waar schepen gebouwd en gerepareerd werden.

Klinische onderzoeken

De laatste dag werden er klinische onderzoeken besproken.


· Eén van de presentaties gaf een overzicht van gen therapie bij andere genetische aandoeningen.
· Voor SCA38 loopt er een onderzoek met docosahexaeenzuur.
· Exon skipping bij SCA (onderzoek uitgevoerd in Leiden).
· TALEN of CRISPR gen editing SCA3.
· Effect van acetyl-DL-leucine in cerebellaire ataxie.

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$1 million grant for ataxia research

A Chapman University School of Pharmacy junior faculty member has been awarded a $1,059,867 grant by the National Institutes of Health (NIH) for ataxia research.


Ataxia is a degenerative, hereditary disease of the nervous system. Those diagnosed often experience the same symptoms as someone who is drunk, such as slurred speech, stumbling and falling. All are related to deterioration of the part of the brain that is responsible for coordinating movement.


The disease can be fatal within 10 to 15 years of the onset of symptoms and can affect people of all ages. There are currently no effective treatments or cure for the estimated 150,000 Americans diagnosed due to the unknown origin and development of the disease.


With this grant, Chapman Assistant Professor in ion channel pharmacology, Miao Zhang, Ph.D., will be able to further their research to develop new drug treatments for movement disorders.

“This innovation award allows us to take further action to identify the underlying causes of ataxia,” Professor Zhang said. “These SK ion channels have been associated with ataxia, although their exact role is not clear. Drugs that enhance SK ion channel activity have shown promise for treatment in past studies.”

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 Chapman University December 15, 2017

Hope for treating currently-incurable neurodegenerative diseases?

What started more than a decade ago as a hunch among a small group of San Diego researchers has grown into real hope for treating currently-incurable neurodegenerative diseases.

Next year, Ionis Pharmaceuticals is expected to release clinical trial results for Huntington’s and Lou Gehrig’s (ALS) diseases that use designer DNA drugs to mute the mutant genes responsible for causing patients’ nervous systems to gradually go haywire.


If early trial results show a reduction in levels of the harmful proteins believed to cause these diseases, then larger trials are likely to follow providing a new path to fight life-stealing conditions that, for all of human history, have remained untouchable by medicine (like ataxia).


While positive results are far from certain, Ionis already has a serious proof-of-concept in Spinraza, a drug approved late last year that uses a similar but not identical approach to successfully treat a neurological condition that kills one in 1,000 children before they reach their second birthdays.


The big deal here is that Ionis has been able to show success working on the far side of the blood-brain barrier, a protective shield of sorts that automatically filters out most drugs injected into the bloodstream, making targets in the brain and spine extremely difficult to hit. The blood-brain barrier requires these drugs to be injected directly into the cerebrospinal fluid, and most thought such an approach would result in drugs simply floating around doing nothing.


So, if early-phase results, the first of which are expected in January, show that these DNA drugs — formally called “antisense oligonucleotides” — can reduce harmful proteins in nerve cells, well, that will be a very big deal indeed, especially because Spinraza has already proven that Ionis chemists have found ways to make these drugs last long enough in patients’ systems to create viable long-term treatments.


The key to early success in animals that has allowed further work in human patients has been the ability to prove that these drugs do get sucked in by nerve cells and that chemical wizardry performed in Ionis’s huge labs has made the drug stable and durable enough to last long enough to bond with passing mRNA strands.


The efficacy has amazed everyone. We don’t get two hours of efficacy. We don’t get two to three days. We don’t get two or three weeks. We get three or four months. The drug lasts a really long time. That means that patients could theoretically come in a few times a year, get a shot in the spine, and go home.


So, are similar results coming for Huntington’s and ALS given that they use the same designer DNA approach in a different way?

At the moment, all results are still blinded, and researchers don’t know what’s coming.

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http://www.sandiegouniontribune.com/news/health/sd-me-dnadrugs-update-20171026-story.html
26 November 2017