Research Updates - Rare Disease Day 2018

The theme for Rare Disease Day 2018 was research, continuing on from Rare Disease Day 2017! Rare disease research contributes to the development of diagnostic tools, treatments and cures, as well as improved health and social care for patients and their families. The patient community needs researchers. They discover diseases and develop treatments and cures. Researchers also need patients and reply upon their participation to ensure research is meaningful. The PURA Syndrome Global Research Network provided research updates for the PURA community on Rare Disease Day  Some new research, some ongoing research.... continued progress and understanding for the PURA syndrome community.

Understanding PURA syndrome using iPSC 
Munich, Germany

Induced pluripotent stem cells (iPSC) are very different from embryonic stem cells. iPSC are generated from human skin cells and therefore do not raise ethical concerns when used for research. They can be “reprogrammed” to become differentiated cells such as neurons (brain cells) or muscle cells. No studies will be performed in humans.

 

We will "reprogramme" the induced pluripotent stem cells to become neurons (brain cells). With the help of genome editing such as CRISPR-Cas9, we will introduce PURA mutations into the genome of some of the induced pluripotent stem cells and then compare them. This direct comparison between cells with and without PURA mutations, in test tubes, will help us to understand the changes PURA mutations cause, for instance in cell communication and their metabolic/chemical state.

The long term goal is to understand on a molecular level what exactly malfunctions in patients with PURA syndrome. This will also support the development of new approaches for treatment.

 

Prof. Dierk Niessing
Lena Molitor

Institute of Structural Biology, Helmholtz Zentrum München,

Germany

Making IPS cells. Source: learn.genetics

Research Update - Ongoing Research 


A PURA mouse model

Philadelphia, USA

Researchers can use animal models to help better understand disease. To help us better understand PURA syndrome, researchers in Philadelphia have created a line of transgenic mice, PURA syndrome mice, that are missing only one copy of the PURA gene (called PURA heterozygous mice). They have one normal PURA gene and one deleted PURA gene.  These mice are similar to PURA syndrome patients who have a mutation or deletion in one copy of the PURA gene. These mice have problems during development but are able to live and grow into adulthood. The PURA syndrome heterozygous mice have many of the same symptoms seen in patients with PURA syndrome including:
 

• Seizures and seizure-like movements

• Changes in gait

• Developmental delay

• Learning disability

• Movement disorder

• Low muscle tone (Hypotonia)

• Sensory processing issues

 

Because these mice have many symptoms similar to patients with PURA syndrome, researchers can use the mice to study some important aspects of PURA syndrome including:

• Understanding how Pur-alpha normally works in different cells and organs.

• Identifying which cells and organs are most affected in PURA syndrome.

• Examining what goes wrong when only one copy of the PURA gene is functioning properly.

 

Having an animal model in the laboratory is also very important for studies. Researchers can test possible treatments and investigate strategies that may one day be used to cure the disease. Researchers are looking to:
 

• Identify possible biomarkers in the blood for diagnosing and monitoring patients with PURA syndrome

• Test different treatments or drugs to help alleviate some of the symptoms of PURA syndrome

• Test novel antisense approaches to try and restore normal function of the Pur-alpha protein

• Test new gene therapy approaches aimed at correcting gene mutations in the PURA gene

 

Members of the PURA Syndrome Global Research Network are working together to share samples from the PURA syndrome mice for several lines of investigation, including metabolomics studies and mRNA transcriptome analysis. They will be able to compare their results from the PURA mouse experiments to samples obtained from PURA syndrome patients, with the goal of discovering new treatment options for patients with PURA syndrome.

A/Prof. Jennifer Gordon 


Lewis Katz School of Medicine 

Temple University Philadelphia, PA, USA

Research Update - Ongoing Research

 
Identifying metabolic biomarkers
for PURA syndrome


Complex human diseases like PURA syndrome can be studied in animal models, where cellular pathways are examined at a level of detail that is often not possible to do in patients. Mice, with a deletion in the gene for PURA, are similar to PURA syndrome patients who have a mutation or deletion in one copy of the PURA gene.

Using the PURA mouse model, we can study the development of symptoms and look for markers, which can give us important clues about disease progression. We will use state-of-the-art metabolomics technologies to study tiny samples of blood and tissue from mice to identify metabolites, small molecules that are involved in processes such as energy metabolism and protein biosynthesis. We hope to be able to translate these findings to PURA syndrome patients.

Our first step will be proof-of-concept experiments to look for differences in metabolites in the blood of PURA mice compared to normal unaffected mice. This can give us important clues about how neurons and muscle cells work in the PURA mice. Next, we will create a PURA patient sample biobank so we can examine blood samples from patients with PURA syndrome and compare our results with the PURA mice. This information can lead to the discovery of new metabolic pathways affected by PURA mutations, new biomarkers for disease
diagnosis or disease progression, and new potential therapeutic strategies to treat patients with PURA syndrome.

The first step of work, the metabolomics testing of the PURA mice, will be completed in 2018. It is hoped that the PURA patient biobank will be organised in 2018/2019, allowing this next level of research with patient samples, to begin in late 2019.


Prof Jerzy Adamski
Helmholtz Zentrum München, Germany
 

A/Prof. Jennifer Gordon 
Lewis Katz School of Medicine, Temple University Philadelphia, USA

Research Update - Ongoing Research


Antisense Gene Technology 

Southampton, UK
 

The PURA gene contains the blueprint for a protein called Pur-alpha. PURA syndrome patients have one correctly functioning and one faulty PURA gene. The Pur-alpha protein has many important functions in cells, including organizing cell division and regulating other genes, by controlling processes involving mRNA such as transcription and splicing. Researchers are investigating which genes Pur-alpha regulates and what affect the faulty Pur-alpha can have on these genes.
 

Antisense gene technology is a gene altering mRNA production technique, that targets the mRNA step in making a protein. Instead of repairing the DNA encoding the faulty PURA gene, it aims to alter the mRNA, stopping it from making defective Pur-alpha protein that can cause issues in patients.

Researchers in Southampton are planning to undertake research to adapt this technology for PURA syndrome. Short single-stranded pieces of chemically modified nucleotides, (known as oligonucleotides) are inserted into cells. These short strands are sometimes abbreviated as “oligos”. The goal is to attach these to the PURA mRNA and stop faulty Pur-alpha from being produced.

 

To assist with this, researchers will use the PURA syndrome mice to look at transcriptomes (all the messenger RNA molecules made in a cell). Researchers will study and compare transcriptomes from normal unaffected mice and PURA syndrome mice to identify which genes are affected by the faulty Pur-alpha protein.

Applications for research funding to achieve this project are ongoing.

Prof. Diana Baralle
Dr. David Hunt
Dr. Andrew Douglas

University of Southampton, England, UK

The PURA Syndrome Foundation Global Patient Registry will be an international registry that collects genetic and clinical information about children and adults who have one of the following conditions:

·      PURA syndrome

·      A 5q31.3 deletion syndrome including PURA

·      A 5q31.3 duplication including PURA​

A patient registry collects information about patients who are affected by a particular condition. When research is being planned, it is very important that patients suitable for that research can be found and contacted. The best way to ensure that this happens is to make sure that patients’ details are all collected in a single database or “registry” that contains all the information that researchers will need, including each patient’s particular genetic mutation and other important medical information about the condition.
 

A registry can also provide useful information on the natural history of the condition. It can highlight the areas that need to be addressed across a patient’s life span, as well as provide information about new areas that should be researched. The PURA Syndrome Global Patient Registry will allow parents of PURA patients to provide information about their child, as well as allowing their doctors/clinicians to also provide details. A single registry to gather details from all patients worldwide, allows us to find enough patients for meaningful research, increasing our ability to commence the creation and repurposing of potential therapies.

The Foundation's Registry Advisory Committee, comprised of the Foundation President, Foundation Medical Liaison, Foundation Parent Liaison, clinicians and researchers will oversee the Registry's activities and will review all requests for information/data from interested researchers. The Registry Advisory Committee will make their recommendations on each request and report back to the Foundation's Board of Directors. 


The registry will be made available in a number of languages.

Development of the registry is being completed with the support of the Clinical Informatics Research Unit at the University of Southampton, UK.  


Details regarding the Global Patient Registry will be presented at the June 2018 conference in Cambridge, UK 

PURA Syndrome Foundation

PURA Syndrome Global Research Network
Clinical Informatics Research Unit, Southampton UK

PURA Syndrome Global Patient Registry

Southampton, UK

2018 PURA syndrome collaborative
epilepsy research paper

 

The PURA Syndrome Foundation and members of the PURA Syndrome Global Research Network, in collaboration with Filadelfia Epilepsy Research Hospital, have commenced a neurology research paper on PURA syndrome, with a specific focus on epilepsy.  Filadelfia Epilepsy Research Hospital is a highly specialised hospital in Denmark, focussed on the diagnosis and treatment of patients with epilepsy and sleep disorders. 

In 2014, the first PURA patients were described in literature. A combination of symptoms such as developmental delay, low muscle tone (hypotonia), neonatal problems and epilepsy, were reported in children with PURA mutations. PURA patients share symptoms which are common for PURA syndrome. But every patient is unique. 


Unpublished PURA patients across the globe were given the opportunity to be included in a new neurology research paper, with an epilepsy focus.  Both patient clinical information and EEG data will be reviewed. We hope that in gaining a clearer understanding of the epilepsy issues being faced by PURA patients, we can develop better care and treatment options long term for PURA syndrome. This paper is due for publication end 2018/ early 2019.

Filadelfia Epilepsy Research Hospital is a highly specialised hospital in Denmark, focussed on the diagnosis and treatment of patients with epilepsy and sleep disorders. For more information about Filadelfia, please the visit their website.
 

Katrine Johannesen M.D.

Prof Guido Rubboli
Filadelfia Epilepsy Hospital, Denmark

 

PURA Syndrome Foundation

PURA Syndrome Global Research Network

Research Update - NEW research


The PURA Syndrome Biobank - An international

resource for research on PURA syndrome.
 

A Biobank is a repository that stores biological samples for use in research. The PURA Syndrome Biobank will collect samples from patients with PURA syndrome from around the world. The samples collected in the bank will include many types of tissues, such as blood, urine, cord blood, CSF, biopsy tissues and cultured cells. The samples for the Biobank may be collected during routine procedures that a PURA child has undergone, such as during a diagnostic test or during planned blood tests, or may be collected as a patient is undergoing previously planned surgery. These samples will be available for scientists who wish to carry out research studies in order to learn more about PURA syndrome.

 

The Foundation's PURA Biobank Advisory Committee, comprised of the Foundation President, Foundation Medical Liaison, a clinician, a researcher, an ethics specialist and a PURA parent, will oversee the Biobank's activities and will review all requests for samples from the bank.  The requests will be evaluated to determine that the scientific purpose of each study and that the goals of the study are aligned with the Foundation's mission. The PURA Biobank Advisory Committee will make their recommendations on each request and report back to the Foundation's Board of Directors. All samples collected in the PURA Syndrome Biobank will require parental authorization and informed consent and will adhere to all relevant ethical, international and local human subjects regulations.

The PURA Syndrome Biobank samples are critical for important new discoveries that will lead to:  

  • better diagnosis of PURA syndrome;

  • new treatments to alleviate symptoms of PURA syndrome;

  • and ultimately, therapeutic strategies for treating patients with PURA syndrome (eg: antisense and gene therapies).

Planning of the Global Biobank is being completed in 2018 with commencement late 2019 hopefully.

PURA Syndrome Foundation

PURA Syndrome Global Research Network

Research Update - Ongoing Research

 
Pur-alpha Analyses

Munich, Germany

 

Patients with PURA syndrome have genetic alterations (variants or mutations) within the PURA gene. This gene contains the building plan for the protein Pur-alpha and its function is impaired in PURA syndrome patients. To date, it is difficult to predict why Pur-alpha does not work properly in the different patients with PURA syndrome.

 

We are using X-ray crystallography, which is a technique similar to a microscope with atomic resolution, to look at these disease causing variants of Pur-alpha. This approach allows us to understand what effect a particular mutation in the PURA gene has on the protein product Pur-alpha. This could either be a failed protein assembly, or for instance, loss of Pur-alpha’s ability to communicate with its cellular binding partners.

 

We have begun our study with Pur-alpha from insects but recently succeeded in using the human version for this analysis. We also use X-ray crystallography to understand how Pur-alpha interacts with its binding partners and how mutations impair these events.

  

The long term goal is to understand on a molecular level what exactly malfunctions in PURA patients and support the development of new approaches for treatment.
 

Prof. Dierk Niessing
Dr. Robert Janowski

 

Institute of Structural BiologyHelmholtz Zentrum München,

Germany

The PURA Syndrome Foundation is a registered 501(c)(3) charity organization. Information on this website is not a substitute for personal medical advice. Families should consult a medically qualified physician in all matters relating to genetic diagnosis , management, and health . Information about PURA and genetics in general is a very fast moving area and while the information on this website is regarded as the best at the time of publication , some facts may change later .