PhD Seminar: Nika Maani

PhD Oral Examination for Nika Maani
Date: Monday, September 16th, 2024

Time: 11:00 AM - 12:00 PM
Location: SickKids Patient Support Centre (PSC)
175 Elizabeth Street, Toronto, ON
3rd Floor - Compassion Room (03-14-012B)
Or join via MS Teams: [Join the meeting now]
Meeting ID: 291 671 708 831
Passcode: H2u7UZ

Thesis Title:
microRNA-133a as an Indicator of Disease Progression and Treatment Response in a Mouse Model of X-linked Myotubular Myopathy

Abstract:

X-linked Myotubular Myopathy (XLMTM) is a rare pediatric neuromuscular disorder caused by loss-of-function mutations in myotubularin (MTM1). XLMTM is associated with severe disabilities and early death, and is, at present, without effective therapy. As interventional clinical trials for XLMTM gather momentum, there remains a critical need to identify robust biomarkers that reflect disease severity and therapy effect.

I identified a significant decrease in the expression of a small RNA (microRNA) miR-133a in muscle and serum of a mouse model of XLMTM (Mtm1 KO mice). miR-133a is a muscle-enriched non-coding RNA that is involved in muscle development and has emerged as a treatment-effect biomarker and therapeutic candidate in other neuromuscular disorders. miR-133a is also a demonstrated negative regulator of DNM2, holding significant pathomechanistic and therapeutic implications for XLMTM.

I show that miR-133a expression significantly and positively correlates with myofiber size and disease severity in Mtm1 KO mice and is upregulated in response to pre-clinical treatments that rescue XLMTM. Using predictive modelling, I show that miR-133a expression demonstrates a powerful therapeutic response and is a robust classifier for XLMTM with a classification accuracy of 70-90% by linear discriminant analysis in both treated and untreated conditions. Receiver operating characteristic (ROC) curve analysis further demonstrated that miR-133a has high discrimination accuracy for XLMTM (AUC > 0.80).

Moving beyond correlation to test causation, I show that miR-133a overexpression in Mtm1 KO mice using an AAV9-based construct significantly improves survival, myofiber size, muscle strength, and modulates overall body composition in XLMTM.

Taken together, I identify a novel non-invasive, therapy-responsive biomarker to monitor disease and treatment response in XLMTM at a time of great clinical need. I also identify a novel treatment strategy with excellent potential for clinical translation. This work results in completely new knowledge of disease pathogenesis and sets the stage for future biomarker validation and treatment development for XLMTM. (PDF Version)

Keywords: microRNA, X-linked Myotubular Myopathy, Biomarker, Therapeutics