New Hope for Rare Disease Treatments
The number of rare diseases identified increases with each passing year due to the advent of deeper genome sequencing for patients, characterization of metabolic pathways, and identification/stratification of patients that historically were thought to have other diseases.
Just five years ago, there were an estimated 3,000 known rare diseases, and today it is estimated at 7,000 to 8,0001. A classification of “rare” is applied when a condition affects fewer than 200,000 people in the United States. An estimated 30 million people in the United States are diagnosed with a rare disease. The work to identify the specific cause of a rare disease can take years. During this time, patients can experience several severe episodes of decompensation (e.g., seizures, hospitalization, etc.) while the most optimal treatment for their disease is identified. Metabolomics is uniquely situated to identify biomarkers of disease for numerous rare diseases because it can identify the small molecule profiles of individual patients and link the changes to specific genetic mutations. This technology enables the diagnosis of patients quicker so they may initiate treatment in a timelier manner.
A recent study with Spectrum Health and Michigan State University has been published in eLIFE that examined the analysis of several blood samples from a patient with ODC1 deficiency to identify biomarkers of disease as well as effects of treatment for ODC1 deficiency. The patient was the first known patient with the condition. While the disease did not have a specific treatment, the ODC1 gene involvement offered several clues to clinicians leading them to seek compassionate use permission from the FDA for DFMO, or difluoromethylornithine, which is an ODC inhibitor.
Her name is Marlene Berthoud (Marley). She was born with numerous developmental disabilities, as well as some unique physical characteristics like no hair, Dr. Caleb Bupp, a medical geneticist at Helen DeVos Children’s Hospital in Grand Rapids and clinical assistant professor in the Department of Pediatrics and Human Development in Michigan State University College of Human Medicine, identified a causative gene for her rare disease.
Photos by Spectrum Health
Initially the results didn’t mean much, but he knew that the gene mutation involved ornithine decarboxylase, or OCD1. Coincidentally, Dr. Bupp heard a talk by Dr. André Bachmann, professor of pediatrics in Michigan State University College of Human Medicine, in which he was discussing polyamines in children with brain cancer, mentioning a drug called DFMO that inhibits the production of ODC proteins often found in pediatric neuroblastoma patients.
When the two doctors finally connected to discuss Marley’s case, Dr. Bachmann shared that after 25 years researching the ODC1 gene he had never come across a patient with Marley’s gene mutation. But, he had observed something similar in a mouse and when given the DFMO drug, the mouse started growing hair.
Based on these insights, the physicians were determined to secure compassionate use application from the FDA to see if the drug would work for Marley. To secure FDA Compassionate Use application to treat Marley, the doctors had to prove if the drug was clinically effective with a Clinical Laboratory Improvement Amendments (CLIA) certified test that Metabolon offers as part of a comprehensive assortment of quality certifications to meet the diverse needs of our clients.
Through collaboration, clinicians at Spectrum Health and scientists at Metabolon identified several biomarkers of disease associated with this novel disorder. They continued their analysis by examining samples post treatment with DFMO. The samples post treatment showed reduced levels of the same biomarkers elevated prior to treatment, suggesting that DFMO treatment was effective at treating the disease and that metabolomics is a valuable tool to monitor the therapeutic effect and safety. The treatment has been transformational for the patient. Read more: https://msutoday.msu.edu/news/2021/marleys-marvelous-success
With the ability to screen for >1,000 molecules in a single plasma sample, Metabolon’s platform can interrogate a single sample for thousands of diseases in a single platform run. These diseases include dysfunctional metabolism in numerous pathways, including amino acid, lipid, carbohydrate, nucleotide and cofactor metabolism and transport. The disorders can affect different organ systems such as liver, kidney, thyroid and affect neurometabolic function as identified by neurotransmitter metabolites detected in the bloodstream. An untargeted metabolomics analysis provides broad detection of a limitless range of diseases from a single sample.
1 https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases