BPAN researcher develops stem cell model and awaits funding for planned drug screening

BPAN researcher develops stem cell model and awaits funding for planned drug screening

Dr. Paul Lockhart of the Murdoch Children's Research Institute in Melbourne, Australia, says that while his BPAN research has developed an important "brain cell" model using stem cells from affected BPAN individuals, his next step - screening (systematic series testing) of drugs for treatment - is still awaiting adequate funding.

Dr. Paul Lockhart

Lockhart received $60,561 in February 2020 from the 2019 Million Dollar Bike Ride (MDBR) grant program, which US families have supported. He planned to conduct drug screening after his initial findings, but the pandemic led to staff shortages and much higher drug screening costs than anticipated. As a result, he returned $25,814 in unspent funds this spring. That money was added to this year's donations to the University of Pennsylvania-sponsored MDBR and will now help fund two $60,000 BPAN research grants under the current solicitation.

Lockhart says the model he developed using stem cells from BPAN patients will be used to screen 3,000 Food and Drug Administration (FDA)-approved compounds in search of a BPAN treatment. The screening process will require several years of funding to identify drugs that can restore normal cell function, known as autophagy, which is the degradation and recycling in damaged cells.

Lockhart's project was titled "Development of novel human stem cell models of BPAN for disease modeling and drug screening" and was part of a larger project that was the first research on BPAN in Australia. It was made possible by a $200,000 anonymous donation in 2019 in honor of Angus Hunter, who suffers from BPAN. The Hunters live in Melbourne and are actively involved in raising awareness and funds for BPAN research.

Lockhart's team used skin cells from six affected children. These samples were converted into induced pluripotent stem cells (iPSC), which can then be transformed into almost any type of human cell.

The team altered the gene to create an identical, matching (isogenic) iPSC that corrects the genetic change that causes BPAN. The researchers transformed these identical pairs into brain cells in a lab dish and analyzed them to determine what effects the genetic change had on cell structure and function. These biochemical studies examined how well the autophagy process worked in the mutant cells.

Lockhart, who spoke about this work at the 2021 NBIA Disorders Association Family Conference, said that a method was developed from the iPSCs to successfully generate neurons and also glial cells that essentially function normally. This showed that the genetic modification had no significant effect on the cells' ability to survive, to transform into different types of brain cells and to form the connections between cells that are critical for brain function.

In addition, analysis of autophagy metabolism showed that it was not functioning properly in the affected cells compared to control subjects. This finding confirmed that the iPSC model can reproduce what has been observed in other cell and animal models and demonstrates its usefulness as a preclinical model for understanding the effects of BPAN on brain function. Although Lockhart was unable to conduct further studies, his group was able to demonstrate that rapamycin, an FDA-approved drug, can increase autophagy activity in the model.
This preclinical "brain cell" model of BPAN is important, Lockhart says, because it "means that we can generate the brain cell types that are specifically affected in individuals with BPAN. These include cortical neurons, which are important for cognitive function, and dopaminergic neurons, which are important for movement."

Lockhart plans to publish his findings and will conduct a drug screening as soon as funding is secured.

Translation of the original article by Patricia Wood from the September NBIA DA newsletter:

Care guidelines for PLAN/INAD are now in progress

Care guidelines for PLAN/INAD are now in progress

Translation of an English article by Patricia Wood

Thanks to the support of four organizations funding the project, consensus guidelines for the treatment and care of a form of NBIA known as PLAN or PLA2G6-associated neurodegeneration are now underway.

This is the third NBIA disorder for which researchers have developed best practices. The other two are more common forms of NBIA, PKAN and BPAN. PLAN encompasses a wide range of symptoms, and depending on the age of those affected and their symptoms, they can be categorized into one of three subtypes: INAD, aNAD or PLA2G6-related dystonia-parkinsonism.

Four organizations have joined forces to support "Best Practices in the Care and Treatment of People with PLAN". In addition to the NBIA Disorders Association, these are the INADcure Foundation, a US-based non-profit organization that advocates for people with INAD and other subtypes of PLAN, and the NBIA sister organizations Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF) in Italy and Hoffnungsbaum e.V. in Germany.

Picture: Dr. Susan Hayflick from OHSU

Dr. Susan Hayflick of OHSU is the principal investigator, working with her colleagues Dr. Jennifer Wilson as lead author and Allison Gregory, MS, as project director. This group also developed the care guidelines for PKAN and BPAN.

The main aim of this project is to advise clinicians on the best and most acceptable approach to the diagnosis, care or treatment of PLAN and its three subtypes. As INAD is the most common form of PLAN, a major part of the guideline is likely to focus on this subtype.

Best practice will be covered in the following areas: diagnostic assessment, initial treatment, pharmacological and surgical care, monitoring for complications, emergency management, educational support, nutrition, psychosocial support and any other areas identified by participants.

Input will also be sought from other leading PLAN experts, as well as selected parents, caregivers and funding patient organizations. Members of the larger patient and family community and other patient organizations will be invited to review and comment on the final draft of the guideline within two weeks.

The project will take approximately 12 months to produce a draft for publication. The total cost is US$50,308, which consists of staff costs covering the time and labor of the project team with their expertise, project management and coordination. Other costs include publication fees for free public access to the paper and travel costs for presenting the results at two conferences within a year of publication.

Translated from: December Newsletter 2022 of the NBIA Disorders Association, p. 4/5:

Translated with www.DeepL.com/Translator (free version)

INAD gene therapy is one step closer

INAD gene therapy is one step closer

Abridged translation of an English article by Patricia Wood

Work on a gene therapy for Infantile Neuroaxonal Dystrophy, known as INAD, received a major boost in October when a London-based biotech company announced its intention to help bring the therapy to market.

London-based Bloomsbury Genetic Therapies Limited, known as Bloomsbury, is to advance its efforts with the help of £5 million seed funding from the UCL Technology Fund. Bloomsbury is working on an adeno-associated virus (AAV)-based gene therapy called BGT-INAD for the treatment of INAD.

INAD is a form of PLA2G6-associated neurodegeneration or PLAN, which usually occurs between the ages of 6 months and 3 years and progresses rapidly. Many affected children do not survive their first decade of life. (...)

Bloomsbury benefits from the expertise of its academic scientists in the fields of gene therapy and rare diseases, including Professors Manju Kurian and Ahad Rahim from University College London. Kurian and Rahim have been working on a gene therapy treatment for INAD for eight years. The NBIA Disorders Association awarded the researchers a grant of USD 150,000 in 2014 to begin their work. This was followed by 655,000 pounds from the UK Medical Research Council.

Image: Researchers from University College London at the 8th International NBIA Symposium in October 2022, where they presented their work.
L-R: Professor Ahad Rahim, Dr. Apostolos Papandreou, Dr. Audrey Soo, Professor Manju Kurian, Dr. Robert Spaull.

Rahim presented the promising data for BGT-INAD at the 8th International NBIA Symposium in Lausanne in October 2022. Preliminary results show a significant improvement in survival and behavioral parameters in mice treated with BGT-INAD.

Dr. Audrey Soo, who is part of Professor Kurian's research group at UCL, also gave an update on preparations for a clinical gene therapy trial with BGT-INAD at the symposium. She said the work is based on a large retrospective natural history study of more than 300 INAD patients worldwide. (...)

UCL research has improved knowledge of INAD, including its key features and symptoms. Most importantly, researchers have developed a meaningful disease-specific rating scale for INAD and discovered potential biomarkers for blood and CSF. Once fully confirmed, the biomarkers can be used as outcome measures in clinical trials, accelerating the development and approval of potential treatments for INAD patients. Soo said she will continue the development and validation of INAD biomarkers throughout 2023.

Bloomsbury is working with researchers on an accelerated timeline to advance its gene therapy research programs into clinical trials as quickly as possible. Bloomsbury plans to complete the comprehensive efficacy evaluation for BGT-INAD in the INAD mouse model in the first quarter of 2023. The company will then focus on the required animal safety testing. It hopes that the accelerated clinical trial design will shorten the time to approval by regulatory authorities such as the European Medicines Agency or the US Food and Drug Administration so that it can make the therapy commercially available to treat patients.
Bloomsbury keeps its website up to date so that patients and relatives can find the latest information at https://bloomsburygtx.com about the latest developments. (...)

Full original version of the article and image source in the December 2022 newsletter of the NBIA Disorders Association, p. 6/7):
Translated with the support of www.DeepL.com/Translator (free version)

Two MPAN project grants totaling $140,000 awarded

Two MPAN project grants totaling $140,000 awarded

Hoffnungsbaum e.V. has awarded two MPAN Fellowships in partnership with three sister organizations in Europe and the U.S. to advance research priorities in the field of mitochondrial membrane protein-associated neurodegeneration (MPAN) identified during an expert workshop on MPAN. MPAN is one of the four most common suptypes from the disease group, the generic term of which is "neurodegeneration with iron storage in the brain".

Dr. Lena F. Burbulla of the Ludwig-Maximilians-University in Munich and Dr. Rajnish Bharadwaj of the University of Rochester in New Jersey (USA) each received one-year research grants of $70,000 to study MPAN.

The financing was made possible by an international cooperation involving Hoffnungsbaum e.V. the NBIA Disorders Association in the USA, Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF) in Italy and Stichting Ijzersterk in the Netherlands were also involved.

In a workshop at the end of 2020 led by Dr. Francesca Sofia, founder and CEO of Science Compass in Milan, Italy, the researchers jointly discussed a research strategy for MPAN based on existing research data and evaluated strengths, challenges and trends in MPAN research to establish a set of scientific priorities. Details can be found here: https://www.hoffnungsbaum.de/aktuelle-ausschreibung-einer-mpan-foerderung/


Dr. Lena F. Burbulla from the Ludwig-Maximilians-University in Munich

Mitochondria, dopamine metabolism and alpha-synuclein

Burbulla's research involves modeling human disease by creating the patient's own cells to discover new mechanisms underlying the pathology of MPAN. To do this, her lab uses induced pluripotent stem cells (iPSCs) derived from skin cells from people with MPAN. Burbulla's team will use these stem cells — which can theoretically be turned into any type of cell in the body — to create dopaminergic nerve cells called neurons, which are known to be affected in the brains of MPAN patients. Dopaminergic nerve cells produce the neurotransmitter dopamine, a chemical messenger involved in regulating body movements, memory, motivation, attention, learning, and more.

Mutations in a particular gene, C19orf12, are the only known cause of MPAN. The function of the gene-controlled protein C19orf12 is still largely unknown. Using disease modelling approaches, the researchers will use a patient-specific model to investigate the function of the C19orf12 protein, in particular how the loss of this protein affects brain cells. Burbulla and her team want to find out how the loss of C19orf12 function affects the health of the mitochondria in these patients' nerve cells. Mitochondria are the "powerhouses of the cell" that produce about 90% of the energy cells need to survive. When mitochondria are damaged, it can have catastrophic consequences for the cell, triggering a series of toxic events that eventually lead to the death of the nerve cells. Since the C19orf12 protein is known to be associated with mitochondria, its loss of function could affect mitochondria and have far-reaching effects on cell health and resilience.

The stem cell model will allow the researchers to compare the MPAN cells with healthy cells and better understand the role of the protein. They will also look beyond the mitochondria for disease-related pathology and study possible changes in the processing of the neurotransmitter dopamine in these nerve cells, as well as a protein called alpha-synuclein, which is known to pathologically accumulate in the brains of MPAN patients.

Alpha-synuclein is located at the ends of nerve cells in the synaptic cleft – the area between neurons where neurotransmitters are released to relay messages throughout the body. Abnormally shaped or excessively abundant alpha-synuclein leads to aggregation or clumping of proteins and inhibits the normal function of neurons.


Dr. Rajnish Bharadwaj from the University of Rochester in New Jersey (USA)

Knockout Flying, Lipid Metabolism and Mitochondrial Function

Baharadwaj's research will focus on better understanding the proteins produced by the C19orf12 gene. His team will use models of fruit flies that have been genetically engineered to lack the CG3740 and CG11671 genes, which correspond to the C19orf12 gene in humans.

Previous studies by other groups and his ongoing work have shown that the fly models have a shorter life expectancy, movement deficits, and a loss of neurons in the brain and retina. This suggests that the fruit flies are a promising model for studying NBIA.

The team's studies also suggest that C19orf12 is a membrane junction protein that may be involved in communication between organelles, specialized subunits within the cell, such as the endoplasmic reticulum and lipid droplets (fats). In the cell, the endoplasmic reticulum is responsible for producing proteins and is involved in the production and storage of lipids.

The team's goal is to investigate how the C19orf12 protein is involved in lipid metabolism and mitochondrial function. Lipid metabolism is the process of producing and breaking down lipids or fats in cells. The researchers want to uncover this role in the brain and other organs. Both lipid metabolism and mitochondrial function are also involved in other forms of NBIA.

Overall, the creation and study of these disease models and the research based on them will improve the understanding of MPAN and pave the way for the much-needed development of treatments.


Source: Article "Two MPAN grants worth $140,000 awarded to further disease insights" in the NBIA Disorders Association's December 2022 newsletter. We thank you for your kind permission to use the content of the article. Translations using the free version of https://www.deepl.com/translator

October 12, 2022, online lecture: Understanding hereditary developmental disorders better - what you can learn from the natural course of the disease

October 12, 2022, online lecture: Understanding hereditary developmental disorders better - what you can learn from the natural course of the disease

Steffen Syrbe is a pediatric neurologist and Professor of Pediatric Epileptology at Heidelberg University Hospital. He has been working with children with neurodevelopmental disorders for over 15 years. During this time, he has developed a strong interest in the genetic causes of epilepsies and neurological disorders. He has helped describe various neurological genetic diseases and identified new genetic causes. Currently, one focus of his scientific work is the translation of basic research into new therapies.

A better understanding of hereditary developmental disorders - what can be learned from the natural course of the disease, using the example of BPAN

In order to be able to develop new therapies from the findings of basic research, it is important to understand the natural course of developmental disorders. Only if we know the natural course of the disease can we assess whether interventions are effective.

An overview of all online lectures can be found here: Online lectures

Prof. Dr. med. Steffen Syrbe

Outpatient clinic for children with therapeutic epilepsy at the Heidelberg Social Pediatric Center

More info...





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