The main focus of our research is to find ways to overcome the negative effects of nonsense mutations on gene expression. A nonsense mutation is a single nucleotide change in the genomic DNA that results in the formation of an in-frame premature termination codon (PTC) in the open reading frame of the transcribed mRNA.

A PTC severely reduces gene expression by:

  • Terminating translation of the mRNA before a full-length, functional protein   can be generated;
  • Triggering nonsense-mediate mRNA decay, a conserved eukaryotic mRNA surveillance pathway that degrades mRNAs containing a PTC, reducing the pool of mRNA available for translation.

Together, these two PTC-mediated mechanisms often reduce protein expression to such an extent, that a disease state arises.

We are exploring ways to overcome the effects of PTCs in order to restore the expression of full-length functional protein at levels that are sufficient to alleviate the phenotypes associated with many genetic diseases. Significantly, nonsense mutations comprise 11% of all gene lesions. Approximately 30 million patients world-wide carry a nonsense mutation.

Nonsense Suppression Therapy

One way we are exploring to overcome the effects of nonsense mutations on gene expression is to suppress translation termination at PTCs using pharmacological agents. For example, we have previously found that certain aminoglycoside antibiotics can suppress termination at PTCs and restore functional protein. We are collaborating with multiple academic and industry groups to identify new compounds that are capable of suppressing PTCs. Eventually, we hope to develop some of these compounds as a treatment for a wide range of genetic diseases.

Inhibition of Nonsense-Mediated mRNA Decay (NMD)

Another way we are exploring to overcome the effects of PTCs on gene expression is to inhibit NMD, a pathway that degrades PTC-containing mRNAs. While inhibition of NMD alone may not restore enough gene expression to alleviate many genetic diseases, attenuating NMD may enhance PTC suppression by elevating the pool of PTC-containing mRNAs available for translation. We are collaborating with researches in academia and industry to examine a number of NMD-inhibiting molecules for their ability to inhibit NMD and enhance PTC suppression.

In addition, we have recently generated a novel mouse model to examine NMD inhibition more thoroughly in vivo. This is important because in addition to degrading PTC-containing mRNAs, NMD also controls expression of about 10% of the mammalian genome, which are essential for normal embryonic development and development of the immune system.

Mucopolysaccharidosis I-Hurler (MPS I-H)

The primary disease model in which we are exploring nonsense suppression therapy and NMD inhibition is MPS I-H, a lysosomal storage disease caused by the loss of the enzyme, alpha-L-iduronidase, encoded by the IDUA gene.

We have made a mouse model of MPS I-H that carries a point mutation that is homologous to the IDUA-W402X nonsense mutation found in MPS I-H patients. This mouse model recapitulates many of the biochemical, morphological, and functional phenotypes observed in MPS I-H patients.

MPS I-H is an ideal model to examine nonsense suppression and NMD inhibition because:

  • ¬†More than 70% of MPS I-H patients carry a nonsense mutation, with the W402X mutation being most common;
  • Less than 1% of normal alpha-L-iduronidase activity can significantly alleviate the severity of the MPS I-H phenotype;
  • Current treatments for MPS I-H are unable to alleviate all phenotypes, particularly in the brain, bone, eye, and heart. Nonsense suppression therapy utilizes low molecular weight compounds that can penetrate these tissues and may alleviate MPS I-H phenotypes in these recalcitrant tissues.

 Other Genetic Diseases We Are Studying

In addition to MPS I-H, we have also established collaborations to study nonsense suppression therapy and NMD inhibition in other genetic diseases, including:

              –Rett syndrome

              –FOXG1 deficiency

              –CDKL deficiency disorder

              –Mucolipidosis II

              –Neurofibromatosis I

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