Monday’s afternoon sessions at MDA’s 2018 Clinical Conference focused on advances in personalized medicine, including the latest in precision therapies, genomics, digital health and MDA’s MOVR initiative.

Among the highlights:

Correction of Duchenne muscular dystrophy by genome editing

Leonela Amoasii, Ph.D., from UT Southwestern Medical Center, discussed a vision for gene editing in DMD.

The team at Eric Olson’s lab has developed a series of mouse models that carry the mutations found to occur most frequently in DMD. The team aims to permanently correct these mutations by using CRISPR/Cas9 to induce exon skipping. In this approach, dubbed myoediting, CRISPR/Cas9 gene editing components are designed to remove splice sites in the DMD gene and are delivered to muscle tissue using a viral vector (AAV9). The Olson team has demonstrated correction of a number of DMD mutations in muscle cells derived from patient iPS cells.

The team’s development plan includes:

• In vitro testing in muscle cells derived from DMD patient iPSCs
• In vivo testing in mutation-specific mouse models
• Preclinical studies in large animal models
• Clinical testing in DMD patients

Scaling up genomic diagnosis of muscle disorders

Daniel MacArthur, Ph.D., from the Broad Institute of Harvard and MIT, stressed the importance of genetic testing by starting with a counterpoint — that we are still far from a complete understanding of rare genetic disease. While it’s estimated that approximately 80 percent of all human genes have some associated genetic disease, the vast majority of these disease gene-phenotype links have yet to be discovered. Breaking down these expected disease genes even further:

• Only 15 percent of those (2,937 genes) have been linked to a known disease (4,163 different disease phenotypes)
• 30 percent of genes are predicted to result in embryonic lethality
• 3 percent represent Mendelian conditions which have been genetically mapped but the specific genes have not yet been identified
• 52 percent are genes for which the disease impact in humans has not yet been determined

MacArthur noted that exome sequencing is a “powerful first pass” approach for rare disease diagnosis. It provides deep coverage of greater than 95 percent of all protein-encoding regions for approximately $350. It’s been applied to hundreds of thousands of controls and more than 7,000 individuals from undiagnosed rare disease families. Diagnosis rates vary, at approximately 15 to 25 percent for isolated probands with heterogeneous presentations, and greater than 80 percent for families with unscreened, clinically well-defined disease.

Lessons learned from Myo-Seq, a study of individuals with limb-girdle muscular weakness, include:

• Deep exome sequencing is an effective front-line diagnostic assay for genetically heterogeneous diseases like LGMD
• The majority of disease-causing variants identified were previously unreported; this emphasizes the challenges of variant interpretation
• Diagnoses impact treatment and follow-up care in a small but important fraction of cases — for example, in some instances diseases were diagnosed such as Pompe disease or DMD, for which treatments exist

Despite successes with exome sequencing, it still failed diagnosis in greater than 50 percent of cases. Whole-genome sequencing alone solves only an additional 5 to 10 percent after inconclusive exome sequencing, as these techniques fail to find complex variants (for example, repeat expansions, inversions), non-coding RNA and regulatory elements, oligogenic effects (for example, multiple contributing variants), missense variants of uncertain effect and variants affecting splicing/expression.

There are currently several challenges with the current model for bringing genetic diagnosis to greater numbers of individuals with rare disease.

• Research is currently investigator-centric and based around physical clinical sites.
• Rare disease families are geographically dispersed and many do not have access to research facilities.
• Genomic data is being generated at a massive scale, but these data are isolated by project and inconsistently processed.
• Results generated about a patient in the research setting are too complicated to return for clinical care; many are not returned at all.

Attempts to overcome these challenges are being made with the Rare Genomes project. Through the project, individuals with rare diseases for which onset occurred before the age of 13 years can sign up for genome sequencing, with costs covered by Illumina. Each participant will complete a questionnaire that collects information on demographics, symptoms and notes about whether others in the family may be affected.

Through a rapid open data sharing model, information can quickly be made available to researchers, and new candidate genes are posted immediately on the project website.

Plans include an MDA-specific recruitment arm specifically designed to bring this approach to still-unsolved cases of limb-girdle muscle weakness.

Advancing the role of digital health in neuromuscular disease

Murray Aitken, MBA, from IQVIA Institute for Human Data Science, discussed the increased use of digital health tools, including mobile health apps and wearable sensors, and their anticipated role in improving human health.

Although the trends in digital health innovation across many disease areas show promising results for the effects they can have on patient care, there is more opportunity for applying these advances in neuromuscular disease. It’s anticipated that digital health tools will accelerate progress for these diseases — including the areas of diagnosis, treatments and cures — but its role in this space is as-yet uncharacterized, making it an area of immediate opportunity for advances that could change lives.

Digital health tools coming online include consumer mobile apps, consumer wearables, connected biometric sensors, smartphone cameras, clinical trial patient information collection tools, in-home connected virtual assistants, telemedicine and virtual physician visits, personal health records, Web-based interactive programs, text messaging or email, and health system disease management apps.

Today, consumer mobile apps:

• Inform — provide information about a disease, symptoms, health care professionals, etc., in a variety of formats (text, photo, video)
• Instruct — provide instructions to the user
• Record — capture data entered by user or from sensors
• Display — graphically display user-entered or sensor data
• Guide — provide guidance based on user-entered information, and may further offer a diagnosis, or recommend a consultation with a physician or a treatment
• Remind/alert — provide reminders to the user (medication use, appointments)
• Communicate — provide communication between patients, families and health care professionals

Digital health in the patient journey can play roles in wellness and prevention, symptom onset and seeking care, diagnosis, condition monitoring and treatment.

Spinal muscular atrophy (SMA)

Richard S. Finkel, M.D., from Nemours Children’s Hospital, summarized recent advances in the efficient diagnosis and effective management of SMA and highlighted exciting new medications.

In the two decades following the discovery of the causative SMN1 gene for SMA, several targeted treatments have evolved from preclinical discovery and animal model testing to active drug trials in the clinic. One of these, Spinraza, was approved by the U.S. Food and Drug Administration in December 2016. While it’s becoming widely available around the world, challenges remain, including access issues and complexities involved with drug administration.

The standard of care continues to evolve in SMA, and with new treatments, a modified phenotype may emerge — perhaps influenced even more with the implementation of newborn screening for SMA, which recently was recommended for placement on the recommended uniform screening panel (RUSP).

Supportive care for SMA recently has shifted toward proactive care, which is initiated pre-symptomatically, as opposed to reactive care, which is initiated after symptom onset. The patient still needs to be at the center of care, and someone is needed to coordinate care.

Following on the heels of Spinraza, additional experimental therapeutics are in development and testing: RG7916, Branaplam, Olesoxime and CK2127107. A combination therapy may be needed, but Spinraza serves as a model for how academics, pharma and the FDA can work together to bring these drugs to the market.

MDA MOVR Registry

In 2013, MDA launched the U.S. Neuromuscular Disease Registry to better understand how neuromuscular diseases develop and progress, and to identify which treatments lead to the best outcomes. The clinical data registry collects a wide range of comprehensive data from individuals with ALS, BMD, DMD and SMA who are seen at up to 26 MDA Care Centers, including diagnostic tests, clinical measures and medical interventions. Participation is voluntary, and information collected from the registry is de-identified prior to being shared for use in scientific research.

Now, MDA is expanding the reach of the registry to 50 sites and seven diseases. It has partnered with IQVIA to expand and enhance what is now the MOVR (NeuroMuscular ObserVational Research) initiative. Enhancements include a new infrastructure, with electronic medical record data capture, a digital health module, a user-friendly interface for sites to access their own data and state-of-the-art security protection of data, plus added support to include training on the platform conducted by IQVIA and user support through IQVIA and dedicated MDA staff. Additional features are optimized data collection and the potential to drive clinical research.

The new program is expected to enhance clinical care and facilitate drug development.

Learn more: mda.org/services/neuromuscular-disease-registry

Read the Registry Highlights Report: mda.org/registryreport

Contact: mdaregistry@mdausa.org

MDA is grateful to the following companies for their support of the 2018 Clinical Conference:

• Strength for Life supporters — Biogen, PTC Therapeutics
• Muscle Champion supporters — AveXis, Santhera Pharmaceuticals, Inc., Sarepta Therapeutics

For more information on the MDA 2018 Clinical Conference, check out our highlights brochure.