Girgenrath Awarded Grant to Study Congenital Muscular Dystrophy

08-healthMahasweta Girgenrath, PhD, assistant professor in the Department of Health Sciences and director of the Muscle Disorders and Regenerative Biology Laboratory at BU Sargent College was recently awarded a two-year, $100,000 grant from the congenital muscular dystrophy organization CURE CMD. Girgenrath’s project, “Inhibition of Angiotensin II Signaling in Congenital Muscular Dystrophy Type 1A” will study the effectiveness of a combinatorial approach to treating the disorder, incorporating both the medication Losartan and muscle specific insulin like growth factor-1 (IGF-1).

Congenital muscular dystrophy is a group of diseases causing muscle weakness at birth. Several defined genetic mutations cause muscles to break down faster than they can repair or grow. Muscular dystrophy type 1A (MDC1A) is the second most common form of congenital muscular dystrophy. Patients with this disease have poor muscle tone at birth, extremely compromised neuromuscular function, and are rarely able to walk independently. Most patients with MDC1A succumb to premature death due to either respiratory complications or failure to thrive. Although significant strides have been made towards understanding the molecular and biochemical mechanisms underlying MDC1A, there remains no effective therapy in place to combat this lethal disease.

Girgenrath believes that the complex pathology seen in MDC1A may be the result of dysregulation of multiple cellular functions and processes, meaning that strategies which simultaneously target several of those mechanisms could lead to a reduction of symptoms.

“Very few studies have utilized the power of combinatorial therapy in the context of muscular dystrophy,” explains Girgenrath. “While most MD treatments are single-target therapies, we’re delving into combinations of different therapies to target multiple pathways.”

Girgenrath and her team will use the CURE CMD grant to evaluate the role of the medication Losartan in combination with IGF-1 to ameliorate disease progression in mouse models of congenital muscular dystrophy. Losartan, a traditionally anti-hypertensive medication, has recently been shown to ameliorate fibrotic pathology in disease scenarios. Because MDC1A has a large fibrotic component that contributes to the progression of pathology, the research team believes Losartan will improve muscle health and survivability. Both Losartan and IGF-1 therapies are already clinically available and approved for pediatric use, further substantiating the immediate translational potential of this combination therapy.

Methods include non-invasive techniques such as plethysmography to evaluate respiratory function, as well as MRI to monitor muscle size and inflammatory response. The research team will determine whether their findings from these non-invasive procedures correlate with the severity and amelioration of lung and muscle pathology, respectively. These data will be used to identify meaningful endpoint measures which could serve as potential biomarkers in clinical trials. Additional data applications include helping to replace painful, invasive procedures, such as muscle biopsies, for following a patient’s disease progression and response to given therapies.