Meet the Expert Series: Dr Drago Bratkovic

Introduction and advancements in mitochondrial management

• Drago Bratkovic is a clinician scientist and head of the Metabolic Unit at the Women’s and Children’s Hospital in Adelaide, where he has been for 13 years, with a research interest in the investigation and management of inborn errors of metabolism and the development of protocols for the clinical follow-up of positive newborn screening 01:35.
• Bratkovic has been involved in clinical follow-up for 19 years and has a passion for research, particularly in mitochondrial research 02:08.
• The biggest advancements in mitochondrial management and treatment have been in diagnostics, with patients and families now having a vastly different experience of being diagnosed with mitochondrial disease compared to 10 years ago 02:56.
• Previously, most patients with mitochondrial disease had a clinical diagnosis with some biochemistry to back it up, but not much else, and genetic diagnosis was not available for the vast majority of patients 03:17.

Genetic diagnosis and testing improvements

• The ability to identify gene changes has been really helpful, allowing families to have other children without the fear of having a child with a mitochondrial disorder 03:49.
• The mitochondrial DNA diagnostic side of things has also improved a lot, with the ability to sequence a larger portion of the mitochondrial DNA, previously only about four mitochondrial DNA changes could be tested for 04:07.
• In Adelaide, one of the laboratories was able to sequence about 60 to 70% of the mitochondrial DNA due to the methods being used, which was quite helpful locally 04:30.
• The Victorian BCGS laboratory is one of the few laboratories that performs mitochondrial DNA sequencing, which is a significant development for equity and access to testing 04:42.
• The inclusion of mitochondrial testing in the NBS benefit schedule has improved access to testing for many families, reducing variability across the country 04:58.

Faster diagnostic processes and multidisciplinary care

• The diagnostic process for genetic testing has become much faster, with exome and genome sequencing allowing for quicker results, sometimes within a few days 05:51.
• In Adelaide, a good relationship with the genetic testing laboratory has enabled rapid testing for mitochondrial disease, providing certainty for families with a sick child in an ICU setting 06:28.
• The Mito Foundation’s work, including advocacy, has increased knowledge about mitochondrial disease in the community and medical field, and has helped establish multidisciplinary clinics 07:15.

Support and therapies through NDIS

• The NDIS has been helpful for many families, reducing the postcode lottery effect and improving access to therapies, although it can still be a struggle to get therapies funded and accessed 08:13.
• In South Australia, the NDIS pilot site has seen significant improvements in support, therapies, and access to equipment for families with mitochondrial disease 08:36.

Challenges in specific treatments and multidisciplinary approach

• Despite some progress, specific mitochondrial treatments and management have not changed much in the last 15 years, with the same vitamin cocktail and arginine emergency protocols still being used 09:26.
• A multidisciplinary approach to mitochondrial management has been challenging due to local funding, but it is an area that can be worked on 09:45.
• Many promising therapies have come up for trial but have failed to pass phase 2 or phase 3 studies, although it is heartening that companies are still trying new approaches 10:17.

Overall improvements and the AussieMit Conference

• Overall, there have been significant improvements in the diagnostic space, making it faster, cheaper, and easier to get a diagnosis, and there is a growing understanding of how to manage mitochondrial disease day-to-day 11:07.
• The AussieMit Conference in Melbourne featured a Clinicians Day where managing mitochondrial disease across the country was discussed, with a positive vibe about the progress being made 12:45.

Research and new registries for mitochondrial disease

• Research on Leber’s Hereditary Optic Neuropathy (LHON) is ongoing, with efforts to coordinate a national approach and better understand the number of patients in the country 12:52.
• New registries, such as the Leigh Disease Registry and the Mito Hope Project, are being developed to collect data on mitochondrial patients and facilitate collaboration 13:13.
• The Mito Hope Project is progressing slowly, with recruitment for families expected to start by the end of 2025 13:48.

Mito Hope Project and Mitochondrial Donation

• A lack of information from the UK’s mitochondrial donation project is hindering progress in Australia, as outcomes from this project would inform future decisions 13:56.
• The Mito Foundation is advocating for more clinical trials in Australia, and efforts are being made to bring research institutions, biopharmaceutical companies, and patients together to achieve this goal 17:12.

Potential new therapy and gene therapy exploration

• A potential new therapy targeting the mitochondrial 3243 A>G mutation is being developed by Precision Therapeutics, with plans to start a clinical trial in mid-next year 14:46.
• The therapy aims to destroy mutant mitochondrial DNA and is primarily targeting muscle, with the possibility of the trial being conducted in Australia 15:00.
• Gene therapy using a vector to deliver an enzyme targeting abnormal mitochondrial DNA is being explored, with experience in this area existing in Adelaide and other Australian centers 15:52.

Importance of patient stories and registries for trials

• Presentations from families and people living with mitochondrial disease highlighted the importance of sharing their stories and experiences 16:36.
• Registries, such as the Leigh Disease Registry, are seen as a crucial starting point for increasing the likelihood of Australian-based trials 17:42.

Challenges in capturing adult mitochondrial patients

• Mitochondrial patients, particularly in pediatric clinics, are often well-organized, but adult patients with mitochondrial disease are dispersed among different clinician groups, mostly neurologists and sometimes hematologists 17:50.
• Most clinical trials target patients over 18 years of age, and it is crucial to get a better idea of this patient group and register them so that their locations and identities are known 18:17.
• Individual hospitals and clinical centers may not capture all patients due to lack of funding or visibility, but a registry can help direct patients to the right places and provide useful data for trial companies 18:29.
• In South Australia, nearly 100% of the pediatric population is captured, but the adult side is more hit and miss, with many patients not engaging with services 18:42.

Benefits of registries for clinical trials and patient access

• A registry working with hospitals can help patients access clinical trials and inform them about the trial process and their responsibilities 19:16.
• Knowing the population, their locations, and their conditions is essential for presenting data to trial companies and ensuring that patients are aware of clinical trials and their responsibilities 19:21.

Clinical trial site readiness and team requirements

• Clinical trial sites need to be ready for action, with pre-set teams and necessary resources, such as coordinators, nurses, and specialists 20:36.
• Starting a clinical trial team from scratch can be challenging, and it is essential to know where study groups are and how ready they are for specific types of studies 21:06.
• Gene therapy trials, for example, require teams familiar with handling vectors and regulations around gene therapy 21:53.

Benefits of joining a registry for individuals and the community

• Joining a registry can have personal benefits, such as accessing clinical trials, and can also advantage the community by providing data points and making the country more attractive for clinical trials 23:07.
• Registering can also help with clinical management across the country, inform natural history studies, and provide a starting point for investigator-led studies 24:08.

Importance and benefits of patient-owned registries

• Registries are essential for collecting data on mitochondrial disease patients, and they should be owned and run by patient organizations to ensure data accessibility and control for patients 25:00.
• A well-run registry provides numerous benefits, including the ability for patients to access their data, add or remove information, and have control over it through a patient portal 25:55.

Mito Foundation’s Mito Registry and data validation

• The Mito Foundation’s Mito Registry is available to anyone who has been mentioned as possibly having mitochondrial disease, from suspected cases to confirmed genetic diagnoses 26:34.
• The registry is regularly reviewed to validate the information provided by individuals, and participants have the opportunity to share their diagnosis and maintain it with the organization 27:19.

Multinational collaborations and global initiatives

• Multinational global collaborations in research have shown promising outcomes, such as the Leigh Disease Registry, which demonstrates the potential for cooperation in natural history studies 27:36.
• Global initiatives, including clinical trials, often require large numbers of participants, making multicentre studies across the world necessary, especially for therapies targeting specific genes 28:29.

Potential for national studies and advancements in personalized medicine

• The Mito Foundation has the potential to run national studies on low-cost therapeutics, such as vitamins and co-factors used in mitochondrial disease, but it requires coordination and leadership 29:23.
• Advancements in personalized and precision medicine, including gene therapy, may have a significant impact on treatment, with therapies like antisense oligonucleotides (ASOs) already being used for conditions like spinal muscular atrophy 30:12.
• Antisense oligonucleotides (ASOs) are being developed for therapeutic use, allowing for targeted therapies specific to an individual’s genetic makeup, which is a key aspect of precision medicine 31:08.
• Companies are setting up to develop ASOs for therapeutic use, and “n=1” studies are being conducted to test the effectiveness of specific ASOs on individual patients 31:23.

Precision BioTherapeutics approach and potential for other conditions

• The Precision BioTherapeutics approach targeting the MELAS mutation is promising and could potentially lead to the development of treatments for other mitochondrial DNA changes 32:32.
• If successful, this approach could pave the way for treatments for other conditions, improving outcomes, although there are many “ifs” and uncertainties 32:52.

Timeframes for precision medicine and clinical trials

• Timeframes for the development of precision medicine, CRISPR, and gene editing are uncertain, but it is estimated that it may take five to ten years, with clinical trials taking around two to three years to complete 33:19.
• The clinical trial process involves several stages, including patient recruitment, treatment, data gathering, and FDA approval, which can take several years 33:56.

Research on the eye as a target for mitochondrial disease treatment

• Research is being conducted on the eye as a target for treating mitochondrial disease, particularly for conditions such as LHON, due to its accessibility and the importance of vision loss as a symptom 35:30.
• The eye is an attractive target for gene therapy and other treatments due to its accessibility and the potential for treatments to reach the back of the brain 35:45.
• Targeting the eye may also provide a proof of concept for therapies that could be applied to the brain, potentially leading to treatments for conditions affecting memory, movement, and other brain functions 37:22.

Connecting families with research opportunities

• Families wanting to be part of research for a specific type of mitochondrial disease can connect with research opportunities through their clinician, who can advocate on their behalf and help them find relevant studies 38:10.
• Clinicians can also help families contact researchers directly, as researchers are more likely to respond to emails from clinicians than from families 39:50.
• Families can also reach out to researchers directly by finding their contact information in published articles, as researchers often have a specific interest in the gene being studied 38:49.
• Being part of a registry is another important step, as it helps researchers collect data and find patients with specific gene changes 39:15.
• Supporting bench researchers by encouraging them to apply for grants, such as those from the Mito Foundation, is crucial for advancing research 40:38.
• Families can also contact organizations, such as the Mito Foundation, for help finding research opportunities and advocating for research funding 41:15.

AI in research and clinical settings

• AI is being used in research to filter through variants, look at drug targets and libraries, and compare thousands of compounds to find one that binds to a mutated protein or DNA 42:01.
• AI is also being used in clinical settings to match lists of symptoms with diseases intelligently, making diagnosis easier and faster 43:13.
• Clinicians can use AI platforms, such as Open Evidence, to quickly search through journal articles and find relevant information, saving time and allowing for more focus on patient care 43:28.

Clinical trial process and non-disclosure agreements

• Individuals wanting to join a clinical trial should be aware of non-disclosure agreements and can expect to be asked to fill out registry forms or surveys, which can be relatively straightforward 45:25.
• Non-disclosure agreements (NDAs) are typically between clinicians and companies, involving the sharing of preclinical work about a therapy, including its mechanism of action and studies done in animals, to ensure the trial looks promising before involving patients 45:27.
• Companies keep this data private during development, which costs millions of dollars, and NDAs ensure this information isn’t publicly disclosed 46:23.

Understanding the clinical trial process and patient responsibilities

• For individuals, understanding the clinical trial process is important, as trials can be intensive, involving frequent visits, tests, and sometimes invasive procedures 46:37.
• Being aware of the responsibilities and what to expect helps reduce anxiety and ensures participants are well-prepared 46:38.
• It’s crucial to stay informed about the trial’s progress and any updates from the research team 46:40.

Clinician review of trial protocols and patient information

• Clinicians review the trial protocol to ensure it’s acceptable to patients, reasonable, and likely to show positive results 46:48.
• Generally, companies have done their homework well and designed the studies well, but occasionally, clinicians may suggest additional considerations 46:52.
• By the time companies come to clinicians, the studies are usually well-established 47:12.
• Clinicians may ask companies for permission to share preclinical data or use published literature to inform patients 47:17.
• Companies need to make a profit from the therapeutics they’re developing, and proprietary information doesn’t interfere with clinicians’ ability to inform patients 48:04.
• Clinicians distill information to patients in the studies, providing an idea of what the therapy does and what it looks like 48:24.
• Some preclinical information is included in the patient information sheet and consent form 48:33.

Non-disclosure agreements and patient safety

• NDAs don’t make the study unsafe; they just protect the companies, and patient safety is the number one priority for clinical investigators 48:51.
• The investigator and their team focus on patient safety and wellbeing, ensuring the protocol is run properly, with patient safety always coming first 49:31.
• If any safety signals come up, the clinical trial team will inform the company and prioritize patient safety 49:45.
• The clinical trial team will look after patients every step of the way 50:01.

Helpline and support resources for mitochondrial disease

• Viewers can reach out to the helpline for questions about mitochondrial disease, getting support, and access, and can also utilize the Pathways Telehealth Nurse Service for health navigation and the NDIS Navigator for NDIS challenges 50:31.

Encouragement and optimism for future therapies

• The research landscape for mitochondrial disease is encouraging, with companies still working towards developing therapies for patients, despite some being financially driven and others being altruistic 51:19.
• It’s essential not to be discouraged by the lack of success in clinical trials over the last decade, as trials may start succeeding soon, having a significant impact on patient care, although it may take two or three years for the results to become mainstream 52:02.
• Patients are encouraged to get their name in registries, such as the Mito Registry, and inform their doctors about their interest in being involved in trials, which can be discussed at each consultation 52:33.
• Despite the need for realistic timeframes and understanding of who the trials might be relevant for, there is optimism around the progress being made, with opportunities to repurpose unsuccessful trials and a focus on outcomes from the people involved 53:35.

Closing remarks and acknowledgements

• Drago expressed his appreciation for being a part of the event and sharing his expertise, thanking the host, Toni, for keeping him on track during the discussion 54:28.