INAD gene therapy moves one step closer

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.

 London researchers
 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.

CoA-Z Trial Update

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

By Allison Gregory

 December 2022

 Allison Gregory
 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.

PLAN Care Guidelines

Care guidelines for PLAN now under development
By Patricia Wood

 December 2022

 Hoffnungsbaum eV

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.

2022 8th International Symposium on NBIA

8th Scientific Symposium on NBIA held in-person in Switzerland
By Patricia Wood

December 2022 

8th Symposium

Meeting in person for the first time since 2017, the 8th International Symposium on NBIA was held in October in scenic Lausanne, Switzerland, on Lake Geneva, attracting 74 participants from 14 countries.

The NBIA Disorders Association has been attending these gatherings of clinicians and scientists since the first one in 2000 — when just 30 people attended — to nurture collaborations and idea exchanges that could lead to new understandings of NBIA and treatments for the disorders.

In addition, our organization since 2014 has been helping by offering travel stipends to early-career scientists who wish to attend the scientific symposium but couldn’t otherwise afford it. This year, we awarded eight stipends totaling $5,000 to those researchers, all of whom presented research or disease-specific information in poster displays at the symposium.

 NBIA early career researchers
 Early-career researchers who received travel grant awards. L-R: Drs. Rachel Wise, Özgür Öztop Çakmak, Fatima Efendic, Robert Spaull, Audrey Soo, Apostolos Papandreou, Kenta Shiina, Iankova Vassilena.

Several early-career scientists sent me emails afterward saying how valuable the experience was and that it has motivated them to continue working on NBIA. It also gave them ideas for research and helped them forge collaborations with fellow attendees.

I was encouraged to see our next generation of NBIA researchers participating in the symposium, with several of them already doing important work on projects led by principal investigators who our organization has funded.

The symposium was lively with many questions and ideas from the audience. Several new collaborations were created during sessions, with researchers sharing how they wanted to work together on a specific idea being discussed.

The program committee was led by Dr. Thomas Klopstock of the Ludwig-Maximilians University Munich in Germany and included Drs. Susan Hayflick of the Oregon Health & Science University in Portland, Valeria Tiranti of Foundation Neurological Institute C. Besta in Milan and Agnès Rötig of Institute Imagine in Paris. Lay advocacy partner Markus Nielbock of Hoffnungsbaum e. V. from Germany and I were also committee members. A local organizing committee led by Fatemeh Mollet of NBIA Suisse handled registration and made sure the symposium ran smoothly.

In addition to the symposium, the NBIA Alliance, which consists of our organization and nine sister groups in other countries, met with CoA Therapeutics to get on an update on its work. Afterward, the alliance met to discuss more ways to work together and plans to overhaul the alliance’s website. Four organizations had members attending the symposium in person and the rest joined the meeting via Zoom.

 NBIA Alliance reps
 NBIA Alliance Representatives at symposium L-R: Roberta Scalise, AISNAF; Fatemah Mollet, NBIA Suisse; Joost Schimmel, Stichting Ijzersterk; Patricia Wood, NBIA Disorders Association.


Many thanks to biotech sponsors Chiesi, CoA Therapeutics and Travere Therapeutics, along with NBIA Suisse and Hoffnungsbaum e.V. in Germany who helped make the symposium possible.

Plans were made to hold the 9th symposium in 2024, with the location to be determined later.

 8th Symposium NBIA
 Group photo of participants at the 8th International Symposium on NBIA in Lausanne, Switzerland.

Research study results in stem cell model of FAHN

 FAHN Researchers
 Researchers working on FAHN research
at the University Medical Center Rostock.
L-R Dr. Jan Lukas, Dr. Moritz Frech,
Fatima Efendic, and Dr. Andreas Hermann.

A team of German scientists who won a $45,000 research grant from the NBIA Disorders Association in 2020 has successfully produced a stem cell model of FAHN, which researchers can use to better understand the disorder and test potential therapies for this disease.

FAHN, or Fatty Acid Hydroxylase-associated Neurodegeneration, is a rare form of NBIA. The type of stem cell the researchers produced is an induced
pluripotent stem cell, which can be programmed to develop into any type of human cell.

The team developed the stem cells from skin fibroblasts from FAHN patients. This tissue contained copies of the mutated FA2H gene that causes the disease. The special ability of a stem cell to turn into any type of cell in the
body now allows the researchers to generate central nervous system cells affected by FAHN.

The team was led by Dr. Andreas Hermann, along with Dr. Moritz Frech, Dr. Jan Lukas and PhD student Fatima Efendic, of the University Medical Center Rostock. They teamed up with Dr. Sunita Venkateswaran from the University of Ottawa. She provided the skin fibroblast cell lines for the research. 

The research was titled “In vitro disease modeling of Fatty Acid Hydroxylase-associated Neurodegeneration (FAHN): Patient specific induced pluripotent stem cells and their neuronal derivatives as human models of FAHN.”

The COVID-19 pandemic caused delays in completing the work, which is ongoing. Third-party funding through the Center for Transdisciplinary Neuroscience Rostock at the University Medical Center in Rostock, Germany, will allow the project to continue through April 2023.

Researchers plan to create additional induced pluripotent stem cell lines, each carrying different disease-relevant mutations. One focus is establishing protocols for differentiation of these cells into oligodendrocytes. Oligodendrocytes generate the myelin sheath in the central nervous system, which surrounds the nerve cell axons and thus ensures rapid signal transmission. Because degeneration of the myelin sheath occurs in FAHN patients, the team aims to investigate the causes of these disorders of the myelin sheath using the newly established model system.

With a better understanding of the abnormal changes in cell functions that occur during disease progression, the researchers can advance to testing potential therapies to see whether they can reverse FAHN’s effects.

A published paper on the work, “Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg,” is available online. Latest results of the project will be presented at the 8th International Symposium on NBIA, taking place from October 13th to 15th, 2022, in Lausanne, Switzerland.


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