Modified Pentamidine Analogs Used for Treating Myotonic Dystrophy

Description:

Background

Myotonic dystrophy (DM) is an incurable genetic disorder that affects 1 in 8000 individuals worldwide. The laboratory of Dr. Andrew Berglund at the University of Oregon has discovered that Pentamidine and other related Diamidines can reverse the progression of this debilitating disease. Myotonic dystrophy is characterized by difficulty relaxing muscles (myotonia), progressive muscle wasting (dystrophy), neurological symptoms and cardio-respiratory dysfunction (responsible for 70% of patient mortality), among other symptoms. At the molecular level, it is caused by the expression (as RNA) of expanded CUG (DM1) or CCUG (DM2) repeats. The alternative splicing factor MBNL1 is sequestered by the expanded RNA repeats, resulting in mis-splicing of a subset of pre-mRNAs, which then leads to the symptoms of this disease1. Currently, there are no FDA-approved treatments aimed directly at the mechanisms causing DM. Patients are given treatments to manage their symptoms, but which cannot halt or reverse the disease's progression2.

 

Technology summary

To discover small molecules capable of disrupting the molecular mechanisms responsible for DM, Dr. Berglund conducted a screen that identified Pentamidine and other related Diamidines as good therapeutic candidates. These compounds have now been tested in biochemical, cell culture and mouse model experiments and were shown to correct splicing defects and significantly improve myotonia, the hallmark symptom of DM1/23,4. Importantly, these compounds decrease the levels of transcripts containing expanded but not normal CUG repeats4, suggesting some degree of specificity in their mode of action.

 

Technology advantages

Other laboratories are currently testing antisense oligonucleotides (ASOs) in similar experiments. Relative to ASOs, small molecule therapies are typically more effective in systemic delivery and have increased uptake by affected tissues, in particular muscle, as well as simpler, less expensive manufacture. Additionally, Pentamidine is considered an orphan drug in the US and is already approved for treatment of several fungal and protozoan infections (Pneumocystis carinii pneumonia, Candida albicans infections, Human African Trypanosomiasis, Leishmaniasis). Therefore, its pharmacological properties and dosages have been well characterized in humans.

 

Patent status

- US patent issued for the use of Diamidines to treat DM (Application # 12/918696).

- Provisional patent issued for the use of Diamidine derivatives  to treat DM.

 

References

1.  Klein AF, Gasnier E, Furling D. Gain of RNA function in pathological cases: Focus on myotonic dystrophy. Biochimie. 2011 Nov;93(11):2006-12

2.  Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):358-67

3.  Warf MB, Nakamori M, Matthys CM, Thornton CA, Berglund JA. Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18551-6

4.  Coonrod LA, Nakamori M, Hilton CL, Bodner MJ, Haley MM, Thornton CA, Berglund JA. Structure optimization reveals a small molecule that reverses the splicing defects and myotonia in a mouse model of myotonic dystrophy. Manuscript in preparation.

 

Patent Information:
Category(s):
Therapeutics
For Information, Contact:
UOregon Admin
University of Oregon
 
Inventors:
Andy Berglund
Micah Bodner
Keywords: