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​​Dystonia Tips and Research Blog

DYT-1, DYT-6 and XDP dystonias: A conversation with an expert

6/21/2020

 
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Who is Cristopher Bragg?
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DR. CRISTOPHER BRAGG
Dr. Cristopher Bragg is an Assistant Professor of Neurology at Massachusetts General Hospital and Harvard Medical School.  His lab studies cellular mechanisms underlying hereditary dystonias, with a current focus on three forms in particular:  DYT1 dystonia, DYT6 dystonia, and X-Linked Dystonia-Parkinsonism (XDP).  He also serves as the Director of the MGH Collaborative Center for X-Linked Dystonia-Parkinsonism (CCXDP), an international consortium focused exclusively on a rare syndrome that is endemic to the Philippines.
What are DYT1, DYT6, and XDP?
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THAP1 DYT-6 MOLECULAR STRUCTURE
DYT1 and DYT6 are both generalized dystonias that typically develop in childhood or adolescence.  They are often designated as “isolated” or “pure” dystonias, because in most patients, dystonia is the sole or primary symptom.
XDP, in contrast, usually arises in adulthood, most often during the third or fourth decade of life.  Unlike DYT1 and DYT6, XDP combines features of both dystonia and parkinsonism often in a temporal progression.  The pattern that has been documented most frequently consists of an initial focal dystonia that spreads to other body regions— as parkinsonian symptoms also emerge over time.  Some patients, however, may exhibit parkinsonian signs as the first symptom and experience a milder course of disease progression,— and the reasons for this heterogeneity are not yet understood.
What causes these disorders?
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XANDRA BREAKEFIELD PHD
The genetic cause of DYT1 was discovered in 1997 by Drs. Xandra Breakefield and Laurie Ozelius at Massachusetts General Hospital.  It was the culmination of many years of painstaking work that took place long before the human genome was sequenced, when the methods for finding disease-related genes were still in their infancy.   They found that DYT1 patients had a specific deletion in a small stretch of the TOR1A gene, which encodes a protein termed torsinA.  Since that first report, a small number of additional mutations in TOR1A have been found, but the vast majority of DYT1 patients all appear to share the same original gene variant.
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LAURIE OZELIUS PHD
DYT6 dystonia is associated with mutations in the THAP1 gene.  Unlike DYT1, which is caused by the same gene deletion in nearly all cases, DYT6 has been linked to a large number of different mutations in THAP1.  It is not yet known if these different mutations  account for differences in symptoms, as so far there are no clear relationships between variants in THAP1 and patterns of clinical disease.
While cases of DYT1 and DYT6 have been found in multiple patient populations around the world, XDP has arisen uniquely among individuals with ancestry to the island of Panay in the Philippines.  It is caused by the insertion of a long stretch of DNA called a “retrotransposon.”  Retrotransposons come in several varieties, many of which have been derived from ancient viruses that deposited their genetic content into our genomes millions of years ago.  They are considered “mobile DNA” because of their ability to move from one chromosome to another by reinserting copies of themselves into other genomic locations  - a discovery first made by Dr. Barbara McClintock for which she was awarded the Nobel Prize in Medicine in 1983.  All living organisms contain various forms of mobile DNA.  In humans, these elements are scattered throughout our genomes; most are completely benign and have lost their ability to move over the course of evolution.  However, a few types of retrotransposons are still active, and within the Panay population, one such example has become inserted into a gene called TAF1, thereby disrupting its function and causing XDP.
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BREAKEFIELD LABORATORY
Why study these syndromes together?
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XDP DYSTONIA WHICH IS VERY COMMON ON THE ISLAND OF PANAY
Despite the differences between DYT1, DYT6, and XDP, the proteins that are affected in these syndromes play inter-related roles within cells. The DYT6 protein, THAP1, and XDP protein, TAF1, both reside within the cell’s nucleus and regulate how genes are turned on or off, a process known as transcription.  The DYT1 protein, torsinA, acts within the adjacent envelope that surrounds the nucleus and is important for its shape and organization.   Numerous research studies over many years have characterized how torsinA functions within the nuclear envelope and how the mutation that causes DYT1 dystonia may compromise this cellular compartment.  Less is known about THAP1 and TAF1, but recent studies are now revealing how transcription in DYT6 and XDP cells is affected by the dystonia-related variants in these genes. 
The Bragg lab studies these and other dystonic syndromes together by analyzing patient cells and characterizing their patterns of gene transcription, which can reveal cellular pathways that are affected in these cells.  The overall goal of this work is to look for any defects that may be common to multiple forms of dystonia.  If such deficits exist, then they may represent potential targets for designing new therapies that would be of broad benefit to patients with dystonia.

Dr. Edgar Rodriguez weighs in on Gene Therapy for Brain Diseases: A Path for DYT-1 Dystonia

6/3/2020

 
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SCIWORTHY.COM (PICTURE) WHICH HAS GREAT IMAGES AND A GREAT SUMMARY WEBSITE OF THIS TOPIC!
Gene Therapy for DYT-1 Dystonia and other diseases?

We sat down with one the experts on gene therapy for DYT-1 dystonia and other central nervous system diseases and we picked his brain on this topic. The interview was fascinating!


​Who is Edgar Rodriguez?
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Dr. Edgardo (Edgar) Rodríguez-Lebrón has 20 years of experience in the gene therapy space with a focus on diseases of the nervous system. He has engineered and developed gene-based therapies to prevent or reverse neurodegenerative processes caused by the accumulation of toxic mutant proteins. He is currently Scientific Advisor to Tyler's Hope, Chief Science Officer of Andante Biologics and a co-founder of early-stage biotech companies developing molecular therapies for CNS diseases. He holds an Adjunct Faculty appointment at the University of Florida where he trained as a graduate student. Go Gators!

Often, diseases that affect the brain are caused by genetic mutations that prevent the normal function of a gene. In other cases, genetic mutations can cause a gene to ‘gain’ a new function that is toxic to the brain. 


​Gene therapies are a class of medicines designed to specifically (i) replace a missing genetic function, (ii) block a ‘gained’ toxic genetic function, or (iii) limit or enhance cellular pathways to support overall brain function. 
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What is a viral-based gene therapy? 
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  • It is a type of gene therapy that uses a virus as a vector, think a ‘shuttle’ or ‘delivery truck’, to introduce genetic cargo into cells. The genetic cargo is designed to replace a missing gene, or suppress the function of a toxic gene, or modify cellular pathways to support normal tissue function.
  • Viruses are fully optimized genetic machines capable of penetrating into cells and delivering genetic material with high efficiency. One virus capable of delivering genetic material to neurons and other cells in the brain in a safe and effective fashion is the adeno-associated virus (AAV).
  • AAV is a naturally occurring virus that has not been connected to any known human disease or pathology. When used as a gene therapy vector, 95% of the AAV’s natural genetic sequence is removed and replaced with the therapeutic genetic cargo.
  • AAV vectors used in gene therapy can enter the cell and deliver therapeutic DNA but are incapable of replicating and cannot sustain a normal virus infection cycle.

What makes AAV a desirable vector for CNS-targeted gene therapies?
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  • AAV is desirable because:
  • AAV has evolved a natural ability to enter human neurons and effectively deliver genetic material to their nucleus.
  • The genetic material delivered by AAV vectors does not become incorporated into human DNA, i.e. the human genome, and instead remains as a stable, independent molecule within the nuclear compartment of the cell. This drastically lowers the risks associated with randomly inserting pieces of genetic material into the human genome.
  • There are many variants or ‘flavors’ of AAV that differ in their protein capsid shell (i.e. the outer covering that shields and encapsulates the genetic material). This diversity allows scientists to select particular AAV vector variants to achieve effective delivery of genetic material into different cells in our bodies, including neurons.
  • For example, some AAV vector variants can be infused into the circulatory system, cross into the brain, and deliver genetic material to neurons in the central nervous system.

What are some recent major developments in AAV CNS gene therapy?
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Recent developments include:
  • The most important recent development was the approval of 2 different AAV-based gene therapy drug products by the FDA. One of these, Zolgensma made by Novartis, is an AAV gene therapy for the treatment of Spinal Muscular Atrophy.
  • More than 40 clinical studies have investigated or are investigating the therapeutic potential of AAV-based gene therapies in human CNS diseases.
  • Artificial intelligence and machine learning algorithms are now being employed to redesign and engineer the AAV protein capsid shells to generate novel variants with more effective, targeted gene delivery properties.
  • Large-scale manufacturing of clinical-grade AAV vectors is becoming streamlined.
What are some of the major hurdles still being faced by AAV-based gene therapies?
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Hurdles include:
  • AAV vectors are live viruses that can be recognized by the immune system as ‘foreign’ agents.
  • More than half of us have already developed some level of ‘immunity’ to naturally occurring variants of AAV that exist in the population.
  • This ‘pre-existing’ immunity to AAV needs to be overcome for AAV gene therapy vectors to effectively reach their target cells and deliver the therapeutic genetic material before being neutralized by the immune system.
  • To address this challenge, clinicians are testing immunosuppressive drug cocktails that could temporarily put the immune surveillance system ‘to sleep’ while the AAV gene therapy delivers the genetic cargo.
  • At the same time, scientists continue to re-engineer the AAV vector capsid shell to make it be like a stealth genetic delivery shuttle system.

How can an AAV-based gene therapy be used in DYT1 dystonia?
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Applications to DYT-1:
  • DYT1 dystonia is primarily caused by the inheritance of mutations in the TOR1A gene.
  • It remains unclear exactly how mutations in TOR1A lead to dystonia. However, multiple studies suggest that the primary TOR1A mutation, p.302/p.303delE, destabilizes the protein, causing a partial loss of gene function. 
  • The matter is further complicated by the fact that the TOR1A protein likes to self-associate. It appears that in DYT1, when the mutant form of TOR1A associates with the normal form of TOR1A, it impairs the function of the normal TOR1A protein.
  • Based on this important knowledge, researchers are designing and testing AAV-based therapies to (1) enhance the function of the normal TOR1A protein, (2) selectively block expression of the mutant TOR1A protein or (3) enhancethe function of the normal TOR1A protein and simultaneously block expression of the mutant form of TOR1A.

What is on the horizon for AAV-based gene therapies as it applies to DYT1?
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On the horizon:
  • Identification of the neurons and brain regions that are primarily affected in DYT1. This will help guide AAV-based gene therapies by providing ‘the right zip code’.
  • Engineering and discovery of new AAV capsid variants that can more broadly target affected brain regions in the DYT1 brain.
  • Deployment of genetic cargo that can facilitate direct and precise ‘editing’ of the TOR1A genomic sequence to replace disease-causing mutated sequences in the TOR1A gene with non-disease causing sequences.

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Tyler's Hope Foundation was established to advance research for a cure, discover effective treatments and to promote awareness and education of DYT1 Dystonia. 

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  • Tyler's Story
    • Progressional Diary
  • About Us
    • Centers of Excellence >
      • University of Florida's Norman Fixel Institute for Neurological Diseases
      • Duke Health
    • About Dystonia
    • Meet the Team
    • The Research
    • Our Leadership
    • Media Coverage
  • Events
    • Center of Excellence at Duke Health Ribbon Cutting
    • Cajun Crawfish Boil
    • Think Tank
    • The Hope Weekend
    • Season of Hope 5K/15K
    • Webinars
  • Support Us
    • Shop
    • The Hope Brew Coffee
    • Planned Giving
    • Send checks
    • Amazon Smile
    • Giving Tuesday
  • Get Involved
    • Donate Now
    • Add a Signature
    • Volunteer Registration
    • Tyler's Hope Tuesdays
    • Social Media >
      • Facebook
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  • Latest News
  • DIPR - Dystonia International Patient Registry
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