Posted on

New gene therapy gives hope

Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood

Arsen S. Hunanyan, Boris Kantor, Ram S. Puranam, Courtney Elliott, Angela McCall, Justin Dhindsa, Promila Pagadala, Keri Wallace, Jordan Poe, Talha Gunduz, Aravind Asokan, Dwight D. Koeberl, Mai K. ElMallah, and Mohamad A. Mikati

Abstract

Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.

Posted on

The 8th Annual Symposium on ATP1A3 in Disease

The 8th Annual Symposium on ATP1A3 in Disease 2019 will take place 3 – 4 October 2019 at the beautiful and conveniently located Grand Hotel Reykjavík on Iceland.

The host this year is the AHC Association of Iceland supported by an organising committee that consist of European scientists that have been working on ATP1A3 related diseases for many years.

The ‘ATP1A3 Symposium in Disease’ is an important symposium that focuses on one of the key genes, the ATP1A3 gene that is essential for normal brain functioning. Mutations in the ATP1A3 gene has been linked to several neurological diseases, including Alternating Hemiplegia of Childhood (AHC). The ATP1A3 gene encodes the alpha(a)3 subunit isoform of the sodium pump, an ion pump that is present in all cells of the body and help cells to maintain correct ion balance, to support in-and outflux of molecules in the cell. In the brain, the a 3 isoform is specific to nerve cells, the neurons. In most neurons, the a 3 isoform helps to maintain the resting membrane potential and reset the ion gradient after an action potential. Doing this, the sodium pump uses energy from the cells and is the most energy-consuming ion pump in the brain. Therefore, it is not surprising that mutations that alter the function of such a vital pump, is associated with neurological diseases.

Posted on

AAV Project update

March 5, 2019 – Joint message from Cure AHC, AHC Foundation and Hope for Annabel:


To pick an analogy for this second AAV Project update, we would say that it is like preparing for space travel. We have the captain and crew, but before we start the countdown we need to make sure our rocket has a clear target, is thoroughly tested, and is fully loaded with fuel and supplies.
Since June 2018, Cure AHC, AHC Foundation and Hope for Annabel have been collaborating on a gene therapy effort using Adeno Associated Virus (AAV) as a system to deliver functioning ATP1A3 to compensate for the mutated ATP1A3 associated with AHC. This project will require many phases with several steps in each phase to eventually get to a clinical trial. We are just in the first phase of the AAV Project where we are developing a viral vector and testing its effects in mice.
In our last update on January 20th, we shared that the three foundations had funded over $225,000 of preliminary research and development in preparation for the experiments on mice scheduled to start on April 1st. We shared that this next step of mice experiments would cost approximately $500,000.
Our rocket is fueled: Due to the phenomenal fundraising efforts by families, friends and strangers, we are thrilled to share that the 3 foundations have $436,000 in the bank to dedicate to the next steps of the AAV Project! In addition, our international partners from France, Iceland, Ireland, Netherlands, Spain and the United Kingdom have pledged over $110,000 towards the AAV Project. We are absolutely in awe of the support of this AAV Project by the AHC community and beyond!
While we have been able to pool resources to meet and exceed the $500,000 goal for the mouse experiments, please don’t stop your fundraising efforts! The AAV Project is a multi-phased initiative. Our gene therapy project is already attractive to industry and institutions who are offering financial support, and the more we can raise as a community the more we can attract the right institutions and the right capital partners. The goal is to keep our therapy affordable or free for patients and families, and there is much more that we as a community will need to do and fund before we can accomplish that.
Redundancy plans, safety checks, and rocket-supplies: Our therapy is performing very well in initial experiments, but we have concluded that further testing is necessary before we launch our rocket-ship. We are determined to proceed carefully and methodically. Thoroughness is even more important than speed.
There are still two fundamental questions we need to answer before our rocket has “lift-off”: (1) can our rocket go far enough (biodistribution), and (2) is our payload potent enough (viral potency). As a result, we are doing another round of quality-control testing, and we are building the same set of viral vectors using a different production technique as a redundancy plan. To avoid lift-off too early, we need to make sure our therapy will deliver ATP1A3 to the right parts of the brain in exactly the right amounts. We estimate these additional tests will take approximately three months. In addition, the development of the mouse colony for experiments is also seeing some delays. We need the mice to breed quickly to create a large enough colony for our planned tests but breeding mice with AHC is challenging. The upside is that by doing our additional quality control testing, the mice colony will have time to grow as well.
We want to make sure that the families who have embraced this effort are not disheartened. Timeline delays are commonplace for meticulous scientists. We have a rocket-ship that is fully fueled, with a captain and a crew. Take-off is slightly delayed since we have chosen to implement additional tests. We feel an intense responsibility to be excellent stewards of your fundraising efforts to ensure we get the best therapeutic results for our kids.
Families and organizations wanting to support the AAV Project should feel comfortable directing fundraising efforts to one, two or all three of the foundations: Cure AHC, AHC Foundation or Hope for Annabel.
For questions about the AAV Project or specific fundraising efforts, please contact Jeff Wuchich (jeff@cureahc.org), Lynn Egan (lynn@ahckids.org) and Simon Frost (simon@tibercapital.com).

Posted on

AHC Bulgaria joins AHCFE

A warm welcome to Alternating Hemiplegia of Childhood Bulgaria as AHCFE newest member.

3 Bulgarian children have been diagnosed with AHC to date and AHC Bulgaria was formed today

We are looking forward to work with Bulgaria in the quest for a CURE

AHC Bulgaria website will open soon http://www.ahcbg.org

Posted on

AHC in 2017 – Looking back….

The year started with a bang because on International AHC day 18th of January 2017 we will launch a new website dedicated to the documentary Human Timebombs The full film was made available in 10 languages on the site http://www.humantimebombs.com

It is our hope that by making Human Timebombs public the film will help families all over the world get more understanding from people in their community. We also hope that more children will get diagnosis because of the film and that we get more doctors and researchers interested in helping the AHC community find a treatment for this important disorder.

For the families however not much happened to make their life easier in 2017, no new treatments and no discoveries that make them hopeful that they will see a cure in the near future.
We cannot stop fighting though because if we do there will of course never be a treatment for our kids.
We will have to do better, push harder, get more funds and raise awareness so that people will understand how important AHC is, not just for us parents that live and breath this disorder every day but for the world.
The world has to understand the this disorder is the key to finding treatments for many more neurological conditions that will in the end help millions of people all over the world.

Let´s make 2018 OUR year and find a treatment that will improve quality of life for our AHC families.

HAPPY NEW YEAR

Sigurdur Holmar Johannesson
President
AHC Federation of Europe

http://www.ahcfe.eu

Here is a short list of what happened in 2017 for AHC, apart from these publications and events lots of fundraisers were held and new research programs were funded.

• In January the documentary Human Timebombs was released to the public on the website http://www.humantimebombs.com

• In February an article about Diagnosis and Treatment of Alternating Hemiplegia of Childhood was published in Springer: https://link.springer.com/article/10.1007/s11940-017-0444-7

• In April a summary from the International AHC task force was released in Neurology: http://ng.neurology.org/content/3/2/e139.full

• In May an article was released: A novel SLC2A1 mutation hemiplegic migraine with alternating hemiplegia of childhood
https://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=24824604

• In June it was announced that 4 AHC associations funded the INTERNATIONAL AHC REGISTRY
http://www.iahcrc.net/news.html

• Also in June
Sho Yano MD PhD and Kenneth Silver MD published this article:
Alternating Hemiplegia of Childhood: A Physicians’ Guide for Diagnosis http://www.raredr.com/news/ahc-guide-diagnosis

• in September the 6th Symposium on ATP1A3 in Disease took place at the Palace Hotel Tachikawa in Tokyo, Japan.

• 2018 Symposium on ATP1A3 in Disease will take place at the Northwestern University Medical Center, Chicago, Illinois USA on October 13th and 14th (Saturday to Sunday)

http://www.atp1a3disease.org

Posted on

AHCFE is a member of Eurordis

AHC Federation of Europe is a member of Eurordis and volunteers as experts in two groups within Eurordis:

Drug Information, Transparency and Access task force (DITA)

 

The Drug Information, Transparency and Access (DITA) Task Force closely follows the work done by patients and consumers at the European Medicines Agency (EMA) and in the European Network of HTA agencies (EUnetHTA) in the areas of product information, transparency of the regulatory process and access to medicines.

There are 18 volunteer members of DITA, from EURORDIS member patient organisations, led and supported by EURORDIS staff members Francois Houÿez, Director of Treatment Information and Access, Health Policy Advisor and Anne-Mary Bodin, Operations Assistant.

DITA volunteers bring invaluable knowledge of their own rare disease and national health system. Many are patients themselves living with a rare disease.

DITA works and gives input into several EU projects that EURORDIS is involved in and that concern the rare disease patient community.

The task force meets twice yearly with regular telephone conferences and email correspondence to maintain the workflow.

https://www.eurordis.org/content/dita-task-force

AND

RD-Connect Joint Patient Advisory Council (RD-PAC)

RD-Connect is a global infrastructure that links –omics data with clinical data and available biomaterials to better understand rare diseases and ultimately lead to improved diagnostics and treatments. This infrastructure supports rare disease research worldwide, in particular research funded under the International Rare Diseases Research Consortium (IRDiRC) beginning with the EURenOmics and NeurOmics projects.

The importance and success of patient representation in rare disease research project governance has been demonstrated. A Joint Patient Advisory Council (RD-PAC) has been established by EURORDIS in the RD-Connect project (coordinating activities with the EUrenOmics and NeurOmics patient representatives) to inform all project coordinators and partners of issues important to patients and guaranteeing a patient-centric approach throughout project activities.

This group contributes the patient perspective to pragmatic solutions for the ethical, legal and social issues raised by –omics research as well as by the integration and sharing of research results and patient data. The RD-Connect, EUrenOmics and NeurOmics projects are navigating new research territory that requires capacity building and the RD-PAC also serves as a platform for education.

https://www.eurordis.org/content/rd-connect-volunteers

 

Posted on

Four AHC associations fund international AHC patient registry

AHC Associations from the Nederland’s, UK,  Iceland and the international organisation Cure AHC have joined forces to fund the IAHCRC-CLOUD platform which will be operated by the International AHC Research Consortium in collaboration with patient driven AHC associations.


This project is headed by Rosaria Vavassori who is the IAHCRC Data Manager and will be crucial for new studies, trials and collecting of information for the international AHC community.

The IAHCRC-CLOUD platform will be developed by the IEMEST Institute

The IAHCRC International Consortium for the Research on AHC and other ATP1A3 related diseases was created officially on November 2014

The Consortium involves clinicians, geneticists and researchers working at University centres in Europe, USA and Australia; it works in close collaboration with health professionals and patients

IAHCRC-CLOUD Platform is an on-line platform that collects and hosts data from IAHCRC Centers and from external sources and shares them for the IAHCRC Studies and Projects. The registry is Accessible to Researchers, Clinicians and Patients