NBIA NEWS & INFORMATION

2022 Million Dollar Bike Ride results in $69,775 for BPAN research

April 2023

Professor Betrand Mollereau of ENS-Lyon in France, was the 2022 MDBR research grant recipient.

Thanks to fundraising efforts by BPAN families and a matching grant from the University of Pennsylvania’s Orphan Disease Center, new BPAN research is now underway to better understand what causes the disease.

Professor Bertrand Mollereau of Ecole Normale Supérieure de Lyon, (ENS-Lyon) in France, received $69,775 as the 2022 BPAN research grant recipient from this annual in-person and virtual bike-riding event.

Mollereau and his co-investigators on the project at ENS-Lyon, Dr. Ludivine Walker and Marion Celle, will spend a year studying autophagy. Autophagy is the cell’s housekeeping and recycling process in which a cell breaks down old, damaged or abnormal parts and reuses some of them to keep the body functioning smoothly. Sometimes, however, the process doesn’t work the way it should.

Defective autophagy has been observed in several BPAN cellular and animal models. Some scientists think insufficient autophagy could be responsible for neurodegeneration in BPAN patients. Hence, a research priority is identifying novel therapeutics that restore the cleaning-and-recycling system.

Collaborating with Mollereau’s lab on the project is Dr. Apostolos Papandreou of University College London. He and colleagues at the Kurian/Ketteler laboratories at UCL have identified small molecule compounds that correct autophagy in certain types of stem cells taken from BPAN patients known as cultured induced pluripotent stem cells (IPSC).

An important step in selecting the best compounds is to show how well they work in an animal model of the disease. For this purpose, Mollereau and co-investigators have developed an animal fly model of BPAN that exhibits hallmarks of the disease, such as an autophagy defect, iron accumulation, neurodegeneration and a movement disorder.

For his part of the project, Papandreou will continue characterizing compounds in IPSC. These cells have unique properties of self-renewal and can be made into many other types of cells. Mollereau and co-investigators will select the best molecule compounds that restore autophagy to these stem cells to see if they can rescue the cellular and movement defects in BPAN flies.

The resulting compounds will then be tested in a larger animal, with a goal of creating a clinical trial to see if one or more of these compounds might benefit BPAN individuals.

Mollereau’s project is titled “Establishing autophagy inducers as novel therapies in cellular and animal models of Beta-propeller Protein-Associated Neurodegeneration (BPAN).”

Two MPAN grants worth $140,000 awarded to further disease insights

 December 2022

The NBIA Disorders Association, along with three sister organizations in Europe, have awarded two MPAN grants that will forward research priorities set during a workshop on Mitochondrial Membrane Protein-Associated Neurodegeneration.

Dr. Lena F. Burbulla of the Ludwig-Maximilian University in Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, each received one-year research grants of $70,000 to study MPAN.

The funding was made possible through an international collaboration that also included the Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF) in Italy, Hoffnungsbaum e.V. in Germany and Stichting Ijzersterk in The Netherlands.

In a 2021 workshop led by Dr. Francesca Sofia, founder and chief executive of Science Compass in Milan, Italy, researchers collaborated to collect data as well as assess strengths, challenges, and trends in MPAN research to establish a set of scientific priorities. For details, see page 8 of our December 2021 Newsletter.

Dr. Lena Burbulla of Ludwig-Maximilian University in Munich, Germany, receives a $70,000 research grant to study MPAN in December.

Burbulla’s research involves human disease modelling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so her lab uses induced pluripotent stem cells (iPSCs) generated from skin cells from people affected with MPAN. Burbulla’s team will utilize these stem cells – that theoretically can be turned into any type of cell in the body – to generate dopaminergic nerve cells that are known to be affected in MPAN patient brains. Dopaminergic nerve cells produce the neurotransmitter dopamine, a chemical messenger involved in regulating body movements, memory, motivation, attention, learning and more.

Mutations in one specific gene, C19orf12, are the only known cause of MPAN. The function of the resulting protein C19orf12 remains largely unknown. Disease modelling approaches will help the researchers examine, in a patient-specific model, the C19orf12 protein function and, most importantly, how brain cells are impacted when this protein is impaired or lost. Burbulla and her team will investigate the effect of loss of C19orf12 function in mitochondrial health in these patient nerve cells. The mitochondria are the “powerhouses of the cell” producing about 90% of the energy cells need to survive. When mitochondria are damaged, disastrous consequences for the cell can occur, along with a toxic series of events that culminate in nerve cell death. Given that the C19orf12 protein is known to associate with mitochondria, its loss of function may affect mitochondria and have wide-ranging impacts on cell health and resilience.

The stem cell model will enable the researchers to compare the MPAN cells to healthy cells and better understand the protein’s role. They will also look beyond mitochondria for disease-associated pathology, probing for possible alterations in the processing of the neurotransmitter dopamine in these nerve cells, as well as a protein called alpha-synuclein, known to pathologically accumulate in MPAN patient brains.

Alpha-synuclein is found on the ends of nerve cells in the synaptic terminals — the area between neurons where the neurotransmitters are released to relay messages throughout the body. Abnormally shaped or overly abundant alpha-synuclein leads to aggregation, or clustering, of the proteins and inhibits normal neuron function.

Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, in Rochester, New Jersey, receives a $70,000 grant to research MPAN in December.

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

Previous studies from other groups and his ongoing work have shown that the model flies have shorter life spans, deficits in movement and loss of neurons in the brain and retina. This suggests that the fruit flies will be a promising model to study NBIA.

The team’s studies also suggest the C19orf12 is a membrane contact site protein that may be involved in communication between organelles, specialized subunits within the cell, such as the endoplasmic reticulum and lipid droplets (fats). The endoplasmic reticulum’s role in the cell is to produce proteins, and it’s involved in the production and storage of lipids.

The team’s goal is to study how the C19orf12 protein is involved in lipid metabolism and mitochondrial function. Lipid metabolism is the process of production and degradation of 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 implicated in other forms of NBIA as well.

Overall, the creation and study of these disease models and subsequent research will advance the understanding of MPAN and pave the way for developing treatments.

INAD gene therapy moves one step closer

By Patricia Wood

 December 2022

Work on a gene therapy for Infantile Neuroaxonal Dystrophy, called INAD, got a big boost in October when a London biotech company announced its intentions to help bring the treatment to market.

London-based Bloomsbury Genetic Therapies Limited, known as Bloomsbury, said it will advance its efforts by using 5 million pounds in seed financing from UCL Technology Fund. Bloomsbury is working on an adeno-associated virus-based (AAV) gene therapy named BGT-INAD for treating INAD.

INAD is a form of PLA2G6-Associated Neurodegeneration or PLAN, and it usually has an onset between the ages of 6 months and 3 years that progresses rapidly. Many affected children do not survive beyond their first decade.

Bloomsbury has three other AAV gene therapy programs in its pipeline and is raising money from investors and other sources to support the timely development of all four programs.

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

University College London researchers at the 8th International Symposium on NBIA in October where they presented their work. L-R: Prof. Ahad Rahim, Dr. Apostolos Papandreou, Dr. Audrey Soo, Prof. Manju Kurjan, Dr. Robert Spaull.

At the 8th International Symposium on NBIA in October 2022 in Lausanne, Switzerland, Rahim presented the promising data for BGT-INAD. Preliminary results show great improvement in survival and behavioral parameters in BGT-INAD-treated mice.

Dr Audrey Soo, part of Professor Kurian's research group at UCL, also presented an update at the symposium to outline preparations for a gene therapy clinical trial testing BGT-INAD. She said the work is informed by an extensive retrospective natural history study with more than 300 INAD patients worldwide.

Also in October, Dr. Amy Geard presented the research findings at the 29th European Society of Cell and Gene Therapy Conference in Edinburgh. She won the 2022 Fairbairn Award for best presentation at the conference by an early-career UK researcher.

The UCL research has advanced understanding of INAD, including its key features and symptoms. Most importantly, the researchers have developed a meaningful disease-specific rating scale for INAD, along with discovering potential blood and cerebrospinal fluid biomarkers. Once the biomarkers are fully validated, they can be used as outcome measures in clinical trials, thus accelerating the development and approval of potential treatments for INAD patients.

Soo said she will continue developing and validating INAD biomarkers over the course of 2023.

Bloomsbury is working with the researchers on an accelerated timeline to bring its gene therapy research programs to clinical trials as soon as possible. It plans to complete comprehensive efficacy assessment for BGT-INAD in the INAD mouse model in the first quarter of 2023. The company will then focus on the required safety tests in animals. It hopes the accelerated clinical trial design will shorten the timeline to gain regulatory approval from the regulatory authorities such as the European Medicines Agency or the U.S. Food and Drug Administration so it can make the therapy commercially available to treat patients.

Bloomsbury keeps its website updated, so patients and families can see the latest developments at https://bloomsburygtx.com.

UCL holds shares in Bloomsbury as part of the intellectual property agreement rights transfer. The UCL Technology Fund is an independent venture capital fund managed by Albion VC. The fund invests in intellectual property commercialization opportunities at UCL.

Update: OHSU CoA-Z in PKAN trial concludes and analysis begins

By Allison Gregory

 December 2022

Allison Gregory, a genetic counselor from the NBIA research group at OHSU, helped manage the CoA-Z trial.

Our NBIA research team at Oregon Health & Science University has concluded the first part of its study of a compound to treat PKAN, called CoA-Z, and will begin analyzing the data to determine its safety, how well it was tolerated, and whether it holds potential as a therapy for PKAN.

Although supply-chain issues brought on by the COVID-19 pandemic caused us to limit the trial’s duration, its home-based, remote design allowed the study to continue without needing to be changed significantly to adapt to COVID restrictions.

The first subjects were enrolled in December of 2019, and enrollment continued through September of 2021. During that time, 77 children and adults with PKAN joined. The study had a high retention rate, meaning most participants were able to continue until their two-year study time had ended, or until the active part of the study ended in summer 2022.

While completing everyone’s participation was a huge milestone, there is still much work to be done. Hundreds of biomarker blood samples collected and frozen over nearly three years are being processed and analyzed in the lab.

Next steps are to check all of the data and collaborate with OHSU statisticians to analyze the information, including data on complications and compliance with the study, and clinical information from the PKANready natural history study that ran in parallel with the trial.

Meanwhile, teams in The Netherlands and the U.K. are moving forward with similar trials. The Dutch team is well along with its trial, and the U.K. team expects to launch in 2023. The trials differ in valuable ways that we hope will provide more information to advance CoA-Z development.

To everyone who participated and has supported the trial, we send our thanks.

Care guidelines for PLAN now under development
By Patricia Wood

 December 2022

Consensus guidelines for treating and managing a form of NBIA known as PLAN, or PLA2G6-associated neurodegeneration, are now underway, thanks to support from four organizations funding the project.

This is the third NBIA disorder for which researchers have created best practices. The other two are more common forms of NBIA, PKAN and BPAN.

PLAN is a broad spectrum of symptoms, and based on an individual’s age of onset and symptoms, they may be classified as having one of three subtypes: INAD, aNAD or PLA2G6-related dystonia-parkinsonism.

Four organizations collaborated to support “Best practices in the care and management of people with PLAN.” Along with NBIA Disorders Association, the others are INADcure Foundation, a U.S. based nonprofit dedicated to helping those with INAD and other subtypes of PLAN, and sister NBIA organizations AISNAF in Italy and Hoffnungsbaum e.V., in Germany.

Dr. Susan Hayflick, with the NBIA research group at OHSU, is the principal investigator of the PLAN consensus guidelines underway.

Dr. Susan Hayflick of OHSU is the principal investigator, working with colleagues Dr. Jennifer Wilson as lead writer and Allison Gregory, MS, as project leader. This group also developed the best practice guidelines for PKAN and BPAN.

The main objective of this project is to counsel clinicians on the best possible and most acceptable way to address diagnosis, management or treatment of PLAN and its three subtypes. Given that INAD is the most common form of PLAN, a greater portion of the guideline will likely focus on this subtype.

Best practice in the following areas will be addressed: diagnostic evaluation, initial management, pharmacologic and surgical management, monitoring for disease complications, emergency management, educational management, nutrition, psychosocial support and any additional areas identified by participants.

Other leading experts in PLAN will also be asked to contribute, along with select parents, caregivers and the funding patient advocacy organizations. Members of the larger patient and family community and other patient advocacy organizations will be invited to review and comment on a final draft of the guideline during a two-week period.

The project will require about 12 months to submit a draft publication. The total cost is $50,308, comprised of personnel costs that cover the time and efforts of the project team with their professional expertise, project leadership and coordination. Other costs are publication fees for free public access to the paper and travel costs to present findings at two meetings within a year of publication.