Researchers at UCL are working on two promising gene therapy treatments for MSUD. The first method uses an optimised gene delivery technology to treat the liver, with the aim of permanently restoring functional metabolism in liver cells for the rest of the patient’s life. The second approach focuses on gene delivery to the brain, to investigate whether restoration of metabolism throughout the brain can alleviate neurological symptoms of MSUD better than treating the liver alone.
The goal of this project is to develop an electrochemical biosensor that can be used for non-invasive BCAA monitoring to provide quick and accessible results for timely treatment decisions. This biosensor will utilize amino acid-specific enzymes to ensure specificity and efficient electron transfer, improving sensitivity for detecting low and high amino acid concentrations.
The goal of this project is to test an adeno-associated viral vector (AAV) gene therapy for MSUD in the calf model. MSUD calves will be treated with human-like doses of AAV gene therapy and fed adult MSUD formula until the AAV gene therapy starts to work. Blood levels of BCAA will be monitored. Behavioral testing, brain MRI, and outcome measures will be performed and compared to unaffected calves. The effectiveness of this gene therapy approach for MSUD in cows will be assessed.
Results will serve as proof-of-concept for this therapy in humans and provide important data to design and plan a human clinical trial for MSUD gene therapy.
The team has developed a mouse model of MSUD to examine psychiatric and learning differences commonly observed in those with MSUD. They have observed significant metabolic differences in the brain of a mouse model of MSUD where the biochemical defect is limited to the brain. This model may help us understand what happens in the brains of patients treated with diet or liver transplantation. Although the mice only have limited behavioral differences, they can serve as an important biochemical model of chronic neurologic MSUD. The team is currently completing long-term brain recordings to see if they can identify abnormal electrical activity in this model. In addition, they are examining the role of an important signaling pathway, mTOR, in the MSUD brain.
This project was supported by the Million Dollar Bike Ride, sponsored by the Orphan Disease Center at the University of Pennsylvania.
Successful transition to independent adulthood requires intact executive and
adaptive function. These neurocognitive domains are frequently impaired in
inherited metabolic disorders (IMD), despite optimal management. For many
IMDs, the impact of executive and adaptive dysfunction on long-term out
comes remains undefined. Standardized assessments linking neurocognitive
status with functional outcomes are needed to improve prognostication and
tailor support for affected emerging adults. Maple syrup urine disease
(MSUD), a relatively prevalent IMD, is primarily diagnosed in the first week of
life through newborn screening. Despite early intervention, executive and
adaptive dysfunction persist. We designed a remote, interactive battery of neu
rocognitive and functional assessments for adults (≥21 years) with MSUD to
correlate neurocognition and long-term outcomes. Participants were selectively
recruited for racial, ethnic, socio-economic, and geographic diversity. Assess
ments completed by 28 adults with MSUD (82% diagnosed after symptom
onset, 25% from minority communities) show a wide range in educational
attainment, employment, and residence. Executive and adaptive function were
significantly impaired in adults with MSUD compared to controls. Executive
and adaptive deficits correlated negatively with educational attainment,
employment, and obtaining skills needed for adult-oriented healthcare or inde
pendent living. Clinical history did not predict functional outcomes, but neuro
cognitive assessments suggest the benefits of pre-symptomatic diagnosis.
Independent adulthood is attainable for individuals with MSUD. Routine
assessment of neurocognition and interventions targeting executive and adap
tive function may improve long-term functional outcomes in IMD.
This project was supported by the Million Dollar Bike Ride, sponsored by the Orphan Disease Center at the University of Pennsylvania.
MSUD affects metabolism in many ways. Improved understanding of the mechanisms by which MSUD affects physical and mental health is an essential step in developing improved treatments. To this end, Dr. Ehud Gazit has developed a model of MSUD in yeast. Yeast is a fungus (think mushroom) made of a single cell. They have used this model to study what happens to cells when they are exposed to toxic levels of branched-chain amino acids (BCAAs), as occurs in MSUD. Their next step will be to try to identify specific compounds which will reduce the toxicity of the BCAAs.
This project was supported by the Million Dollar Bike Ride, sponsored by the Orphan Disease Center at the University of Pennsylvania.
This project sought to develop a muscle directed gene therapy application for MSUD using a mouse model for MSUD. In humans, skeletal muscle is responsible for approximately 60% of the oxidative enzyme capacity compared to an approximately 10% contribution from the liver. Therefore, we evaluated the efficacy of a muscle directed gene therapy approach, compared to one directed to the liver. Results were promising. Future work will examine the efficacy and safety of this approach in primates.
This project was supported by the Million Dollar Bike Ride, sponsored by the Orphan Disease Center at the University of Pennsylvania.
Dr. Wendy Packman and Dr. Indira Mehta from California examined psychosocial issues affecting those with MSUD. The organization assisted financially with the project and the results were published in the Journal of Genetic Counseling.
This project led to the development of NBS Connect, an internet-based registry and support network for parents and individuals with inborn errors of metabolism. The site was managed by staff from Emory University Department of Human Genetics. After several successful years of operation, the project was terminated due to inadequate funding.
Dr. Hutson and colleagues developed a mouse model of Classic MSUD with the aim of understanding the molecular basis for the effects of MSUD on the central nervous system and body metabolism. They previously generated a mouse containing a knockout (KO) of the mitochondrial branched chain aminotransferase (BCATm) enzyme. In this animal BCAA metabolism is blocked at the first step in all tissues outside the central nervous system. This animal provided evidence that branched chain amino acids (BCAAs) have profound effects on body metabolism, independent of their effects in brain and suggested the branched chain keto acids are the primary toxic metabolite in MSUD.