MUSCLE DISEASES

Muscle diseases can be caused by metabolic disorders or other genetic mutations. Muscular dystrophy is the most common form and characterized by progressive weakness and degeneration of the skeletal muscles.

Triangulum brings years of experience in preclinical pharmacology studies of drug candidates in muscle disease areas such as Myotonic Dystrophy Type 1 (DM1). We offer services specific to your needs by conducting efficacy studies with your investigative compounds in various muscle diseases. At present we offer our expertise in the following mouse models.

  • HSALR mouse model of Myotonic Dystrophy Type1 (DM1)

  • In humans DM1 is caused by an expanded CTG (or CUG at RNA level) repeat in the 3′ UTR of DMPK (Dystrophia myotonica Protein kinase) gene. The HSALR (Human Skeletal Actin Long Repeat) transgenic mouse is the widely used model in DM1 research. These mice express high levels of CUGexp RNA in skeletal muscle and have expanded CTG repeat in the 3′ UTR of a human skeletal actin (hACTA1) gene. The CUGexp transcripts are retained in nuclear foci, along with splicing factors in the Muscleblind-like (MBNL) family, and the sequestration of Muscleblind leads to misregulated alternative splicing and these pathological changes affect the muscle function known as Myotonia. The data presented in the figure below show the reduction of foci in the quadriceps muscle in HSALR mice by compound A and Compound B.

    Reduction of Foci in the Quadriceps Muscle of HSALR Mice



    Note: These HSALR mice are available from an academic institution and also cryopreserved at Jackson Labs. Please contact us for more details if your project requires this mouse model.

  • mdx model for Duchenne Muscular Dystrophy (DMD)

  • DMD is caused by mutations in the dystrophin gene resulting in the absence of dystrophin protein. The mdx mouse model for DMD is routinely used to study the efficacy and toxicity of disease modifier compounds. The mdx mouse model does not have a functional dystrophin protein in its muscle since a nonsense point mutation in exon 23 of the dystrophin gene results in the premature termination of translation in dystrophin expression. Nonetheless, the mdx mouse model is extremely valuable in assessing the activity of drugs as well as performing proof-of-concept experiments.

  • Evaluation of drug activity in the muscles of wild type mice

  • Our team also offers preclinical screening services with your drug candidate in normal wild type mice that target muscle. We work with our clients in providing scientific guidance, customized study design, end-point analysis, histopathology services, and will assist you with the interpretation of the data.





Triangulum offers the following CRO services in muscle diseases:
  • Dosing of test compound(s) via IP, SC, and oral routes
  • In-vivo drug screening (efficacy and toxicity) for muscle targeting drugs in wild type, HSALR and mdx mice
  • Histopathology (H& E) services for different muscles types
  • Serum biomarker analysis for muscle damage
  • Coat hanger assessment for muscle strength and coordination


Relevant Publications of our scientists: 1. Wheeler T, Leger, A, Pandey SK, Macleod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton, C. Nature, 2012, 488, 111-117. PMID:22859208

2. Pandey SK, Wheeler TM, Justice SL, Kim A, Younis HS, Gattis D, Jauvin D, Puymirat J, Swayze EE, Freier SM, Bennett, CF, Thornton CA and Macleod AR. Journal of Pharmacology and Experimental Therapeutics, 2015 Nov; 355 (2):310-21. PMID: 26330536

3. Carrell S, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, and Thornton C. Hum Mol Genet. 2016 Oct. 25(19):4328-4338. PMID: 27522499

4. Jauvin D, Chrétien J, Pandey SK, Martineau L, Revillod L, Bassez G, Lachon A, MacLeod AR, Gourdon G, Wheeler TM, Thornton CA, Bennett CF, Puymirat J. Mol Ther Nucleic Acids. 2017 Jun 16;7:465-474. PMID: 28624222