Lex-Schultheis

By  | September 3, 2014

Nearly $80 million has poured into the ALS Association since July 29 due to the overwhelming popularity of the Ice Bucket Challenge, a grassroots campaign to raise awareness and funding for amyotrophic lateral sclerosis (ALS) treatment and research.

Participants in the challenge dump ice water over their heads and donate an amount of their choosing to support the ALS Association or similar foundation, and the campaign picks up steam as participants challenge peers to do the same. Those who fail to complete the challenge within a 24-hour window are asked to donate $100 to an organization benefiting those impacted by ALS.

Prior to the campaign’s viral success, few without a direct connection to ALS may have known the facts about the neurodegenerative disease commonly known as Lou Gehrig’s disease. As such, the campaign has directed a spotlight on efforts put forth to combat ALS, which affects as many as 30,000 Americans at any given moment.

Long before the launch of the Ice Bucket Challenge, Dr. Eva Chin, Assistant Professor of Kinesiology at the University of Maryland School of Public Health, and fellow researchers set out on a mission to develop early diagnostic tools for ALS. Chin, along with Dr. Justin Kwan, Assistant Professor of Neurology at the University of Maryland School of Medicine, and Dr. Lyle Ostrow of Johns Hopkins School of Medicine, have worked to develop a clinical assay for the early diagnosis of ALS, to distinguish between molecular defects in different ALS sub-types and to help develop personalized treatments for the ALS sub-types in the future. The team of researchers will determine which proteins are relevant to patients with ALS and develop a test that uses a muscle biopsy sample that is analyzed for the specific proteins that are defective in ALS. Because no molecular-based laboratory tests for ALS yet exist, the process to diagnose and treat the disease can take 12-18 months to initiate.

“Similar to cancer, the earlier you treat ALS, the more you slow down disease progression,” Chin noted.

According to the ALS Association, the life expectancy of an ALS patient averages just two to five years from the time of diagnosis, although the disease is variable.

Nevertheless, the recent spike in public awareness of a disease that has a tremendous impact on a relatively small population – when compared with certain cancers or heart disease – has demonstrated the need for research benefiting small patient populations, such as those impacted by rare diseases.

As the Ebola outbreak in West Africa and the Democratic Republic of Congo has tragically demonstrated, funding and support for the treatment of rare diseases and medical conditions can be difficult to come by when there are relatively few advocates for the cause. Yet, researchers at the University of Maryland (UMD) and the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) are working to attack many diseases which commonly lack representation and research support.

Since its launch, NCC-PDI has worked to advance orphan products development for a variety of causes impacting pediatric populations. NCC-PDI’s foundation traces back to September 2013, when the Food and Drug Administration (FDA) Office of Orphan Products Development awarded the FDA P50 grant to the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System (SZI) and the University of Maryland A. James Clark School of Engineering to establish NCC-PDI. The 2013 grants were awarded to consortia that brought together teams with excellence and expertise in delivering business, regulatory, legal, scientific, engineering, and clinical services for children. All consortia work collaboratively with the FDA to help innovators effectively navigate existing laws, regulations and agency guidance to protect the health and safety of children.

“It is particularly interesting that NCC-PDI is working so hard to address the needs of small patient populations because many in industry focus resources primarily on large populations, such as those impacted by cancer or heart disease,” said Dr. Lester W. Schultheis, Director, Regulatory Science Initiative at the University of Maryland. “Patients with rare diseases have relatively few advocates interested in the research community despite the compelling harm that these rare diseases cause to individual patients and their families. Therefore, the initiatives put forth by UMD and SZI researchers is significant.

“A secondary benefit, in addition to the potential for NCC-PDI to help the unfortunate few patients with rare diseases, is the opportunity our researchers have to learn about very complex machinery within the human body,” he continued. “The study of rare diseases can inform medical science to improve our understanding of fundamental mechanisms of metabolism that may be relevant for diagnosis and treatment of more prevalent disease.”

One such technology put forth by UMD and Children’s National Medical Center researchers is a point-of-care device to measure blood ammonia levels.

Hyperammonemia, a life-threatening condition, is characterized by elevated blood ammonia levels and causes severe neurodevelopment complications. The condition originates from metabolic disturbances in the urea cycle caused by several different inborn errors of metabolism collectively referred to as Urea Cycle Disorders (UCDs). Following a diagnosis, patients are given strict dietary limitations to reduce protein intake and they are treated with ammonia scavenging drugs. Nevertheless, patients must monitor their blood ammonia levels throughout the span of their lifetime. Without a system in place to allow patients and their caregivers to rapidly measure blood ammonia levels, families endure a great deal of stress as any sign of the patient feeling ill prompts concern of a hyperammonemic episode, warranting a trip to the doctor or emergency room for testing.

Recognizing this, Drs. Peter Kofinas (UMD, Fischell Department of Bioengineering) and Marshall Summar (Children’s National Medical Center) have developed a prototype of point-of-care device for detecting ammonia in a drop of blood, obtained by pricking the finger – or heel for newborns – to be used at home, in clinics, and in hospitals, in a fashion similar to a glucometer. Consolidating this system into a small, easily manufactured device and test cartridge will provide rapid point-of-care detection with minimal training. Additionally, a rapid point-of-care sensor would allow for at home and bedside testing, reducing the large burden on children with UCDs and their caretakers.

The high sensitivity of the developed point-of-care device allows for accurate and reliable differentiation between the colorimetric responses produced by elevated (100-500 mM) or normal (40-70mM) levels of ammonia in blood. Consolidating this system into a small, easily manufactured device and test cartridge provides rapid point-of-care detection with minimal training. It is expected that such sensor device could be used to screen all newborns for diagnosis at hospitals.

The device would also allow families or primary care facilities that have a child or patient with hyperammonemia to frequently monitor ammonia levels and use the results of the test to manage the child’s diet and treatment.

While UMD and SZI researchers work tirelessly to develop diagnosis and treatment options for many of today’s most underrepresented diseases, a great need for continued research and funding remains.

At both the undergraduate and graduate level of study, UMD students continue to work to develop new systems for monitoring rare conditions such as methyl malonic academia – a rare inherited disorder of the metabolism – and tyrosinemia – a serious metabolic disease that is rare in the United States but more common among the French Canadian population.

Expanding beyond the reach of the D.C.-metropolitan area, UMD is collaborating with the Children’s Hospital of Philadelphia to offer educational opportunities to FDA scientists interested in the development and adoption of next-generation sequencing technologies for diagnostic testing of genetic disease, such as in pediatric disorders including hearing loss, epilepsy, Noonan syndrome, Rett syndrome, paraganglioma and neuroblastoma.

Moving forward, NCC-PDI continues to build on its commitment for collaboration and innovation in pediatric device development, and many of the projects undertaken by UMD and SZI researchers promise to make a significant impact on human life, even beyond the scope of pediatrics. While currently, UMD researchers have not formulated a coordinated effort to specifically target rare diseases, recent research trends – both within and outside the university – have indicated this as a recurring theme.