Our Research

Neurons

A major challenge in translating genetic therapies to the clinic for neuromuscular disease is their targeted delivery to the tissue of interest.  The Dowling Lab is interested in developing and testing muscle and neuronally targeted delivery vehicles.

  • Tissue-targeted Adeno-Associated Virus (AAV): The Dowling Lab utilizes induced pluripotent stem (iPS) cell disease models and animal models to test tissue targeted AAVs.

  • Muscle Targeted Lipid Nanoparticles (LNPs): The Dowling Lab is interested in developing LNPs through lipid content optimization and the addition of tissue targeting conjugates.

Based on the  number of genes and the diversity of mutations underlying neuromuscular disease, the Dowling lab is interested in a variety of genetic therapeutic tools that can be adapted to meet the unique needs of patients.

These therapeutic tools include:

  • Anti-sense oligos (ASO’s):  ASO’s can be used to alter RNA splicing to restore reading frames, skip premature stop codons or block the inclusion of poison exons (TANGO; Targeted Augmentation of Nuclear Gene Output)

  • CRISPR modulation of gene expression:  CRISPR activation (CRISPRa) of transcription  can be used for the targeted increase in the expression of healthy copies in haploinsufficient disease.  Conversely, CRISPR inhibition (CRISPRi) can be used to turn off the expression of toxic disease transcripts.

  • Disease allele editing:  Rapidly evolving technologies such as Base Editing and Prime Editing can be used to correct disease causing variants.

  • mRNA delivery:  mRNAs encoding both full length and miniaturized versions of the proteins underlying neuromuscular disease can be used as gene replacement therapies.

  • Modular gene delivery: AAV-mediated delivery of genes encoded over multiple vectors and stitched together via intein mediated trans-splicing can overcome the size limits of AAV-mediated gene delivery and represents a promising therapeutic approach.

  • Synthetic microRNAs:  Synthetic complementary sequences embedded in micoRNA hairpins can selectively trigger the degradation of  mRNA encoding toxic disease variants or other therapeutic targets.

The development of safe and effective therapies to treat neuromuscular diseases depends on a deep multiorgan understanding of tissue development and  the molecular mechanisms of disease.  The availability of relevant disease models aid in confirming efficacy of therapies and identifying potential toxicity.  The Dowling lab works to develop multispecies disease models (iPSC, mouse and zebrafish) for a number of diseases including:  X-linked myotubular myopathy (XLMTM) driven by MTM1 variants, NEB-related nemaline myopathy caused NEB variants, Duchenne Muscular Dystrophy caused by DMD variants, RYR1-related myopathies, Monogenetic autism spectrum disorders caused by a number of unique variants, Pura Syndrome caused by PURA variants, LMNA related myopathies caused by LMNA variants, Myotonic Dystrophy Type 1 caused by DM1 variants.