Maple Syrup Urine Disease (MSUD)
Maple Syrup Urine Disease (MSUD) is a rare inherited disorder caused by an insufficiency in the branched-chain alpha-keto acid dehydrogenase complex. This enzyme deficiency leads to the accumulation of branched-chain amino acids within the body. At our company, we've assembled a team of seasoned professionals with a wealth of experience in navigating drug and therapy development challenges specific to MSUD.
Overview of MSUD
Maple Syrup Urine Disease is an uncommon genetic metabolic disorder marked by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex. This enzyme shortage results in the buildup of branched-chain amino acids and their toxic by-products. This results in a distinctive sweet-smelling urine, along with neurological impairments if untreated. The incidence of MSUD varies globally, with an estimated prevalence of 1 in 185,000 live births, though certain populations, such as the Old Order Mennonites, exhibit much higher rates.
Pathophysiology of MSUD
MSUD arises from a deficiency in the branched-chain α-ketoacid dehydrogenase complex, resulting in the buildup of branched-chain amino acids (BCAAs) like leucine, isoleucine, and valine, as well as their associated keto acids. This accumulation results in the toxic effects seen in MSUD, including severe neurological damage. Figure 1 illustrates the metabolic pathway, showing how the enzyme deficiency interrupts the normal catabolism of BCAAs, leading to their buildup and the subsequent manifestations of the disease.
Fig. 1 Pathophysiology of maple syrup urine disease. (Schwartz, C.E. and Stevenson, R.E., 2007)Biomarker Development of MSUD
Biomarker development is crucial for the early diagnosis and effective management of MSUD.
- Alloisoleucine: Alloisoleucine is a specific and highly reliable biomarker for MSUD. It is a stereoisomer of isoleucine that accumulates in the blood of individuals with MSUD and is not typically present in healthy individuals. This biomarker is particularly useful for differentiating MSUD from other metabolic disorders.
- Branched-Chain Amino Acids (BCAAs): Such as Leucine; isoleucine and valine, elevated SHBG levels in MSUD individuals suggest liver exposure to high T3 levels, indicating tissue-specific thyroid hormone effects.
- Branched-Chain Alpha-Keto Acids (BCKAs): These keto acids are intermediates in the metabolism of BCAAs and accumulate when the branched-chain alpha-keto acid dehydrogenase complex (BCKDC) is defective. High concentrations of these amino acids in the blood are a hallmark of MSUD.
Therapeutics Development of MSUD
Small Molecule Drugs
Small molecule drugs for MSUD aim to manage the metabolic imbalance by either reducing the levels of BCAAs or enhancing the residual activity of the BCKD complex. Thiamine is a cofactor for the BCKD complex. In some MSUD individuals, particularly those with the thiamine-responsive variant, supplementation with high doses of thiamine can enhance the residual activity of the BCKD complex.
Gene Therapies
AAV vectors are used to deliver functional copies of the BCKDHA, BCKDHB, or DBT genes to the liver cells. The liver is targeted because it is the primary site of BCAA metabolism. AAV-mediated delivery of the BCKD genes can restore enzyme activity and normalize amino acid levels. An AAV vector carrying the human BCKDHA gene was able to correct metabolic abnormalities in a mouse model of MSUD.
Our Services
Our company takes a cooperative approach, working hand-in-hand with clients to develop customized and innovative treatment strategies for MSUD. Our focus on customized strategies ensures that we meet your individual needs with the highest level of support and guidance.
Platforms of MSUD Therapy Development
Animal Models of MSUD
We have considerable expertise in developing and employing animal models that accurately replicate the disease characteristics and therapeutic responses seen in MSUD. These models are instrumental in investigating the underlying mechanisms and assessing the safety and effectiveness of prospective therapies with precision.
| Non-Genetically Engineering Models | ||
| Our company offers a range of models specifically designed to meet the unique research needs of MSUD. These models enable researchers to simulate the disease and delve deeply into its pathogenesis and therapeutic development. | ||
| Optional Models |
|
|
| Genetically Engineered Models | ||
| Our expertise in genetic engineering techniques, such as CRISPR/Cas9 enables us to create precise and reliable models to recreate the disease in various model organisms. | ||
| Optional Models |
|
|
| Optional Species | Mice, Rats, Non-human primates, Others | |
Moreover, we provide a variety of detailed animal model services focused on particular signaling pathways and molecular targets.
If you are interested in our services, please don't hesitate to contact us.
References
- Wasim, M., et al., "Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options." Biochem Genet, (2018). 56(1-2): p. 7-21.
- Strauss, K.A., et al., "Branched-chain alpha-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes." Mol Genet Metab, (2020). 129(3): p. 193-206.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.