Therapeutics

Hepatitis C

The hepatitis C virus (HCV) currently afflicts an estimated 3.9 million people in the US and 175 million worldwide. Infection with HCV becomes chronic in 75-85% of individuals, with 70% of those eventually presenting chronic liver disease. HCV is recognized as a major cause of end-stage liver disease such as liver cancer (1-5% of HCV infections) and cirrhosis (10-20%). HCV is the leading indication for liver transplantation in the Western world.

Microscopic view of Hepatitis C Virus particles

Hepatitis C Virus particles

Current HCV therapy, a combination of pegylated interferon-alpha and ribavirin, is only partially effective; of those patients infected with the most common strain, genotype 1, only about half achieve a sustained viral response. Unfortunately, HCV genotype 1 comprises 77% of cases worldwide, and even more in the West. Because the standard of care is associated with severe adverse effects including flu-like symptoms, hematologic abnormalities and depression, patient compliance is poor.

Several new drugs currently in clinical trials inhibit specific viral proteins (protease or polymerase), mechanisms of action that are distinct from those of the standard of care. While some of these drugs show promising interim results, all are vulnerable to the development of viral resistance through mutation. SomaGenics’ shRNA-based HCV drug candidate, now in pre-clinical development, has potent antiviral activity against all common HCV genotypes and is expected to be much less vulnerable to viral escape.HCV SEM image

HCV has many features that make it an ideal target for shRNA-based therapeutics:

  • Chronic, slow viral infection
  • Effective treatment is known to clear the infection
    • No reservoir of silently infected cells is known, unlike with HIV
    • No DNA component as with HIV
  • Target organ (liver) is accessible to i.v. delivery of RNA drugs
    • Provides a platform for subsequent targeting of additional liver or metabolic diseases
  • Cocktail of shRNAs targeting multiple conserved sites minimizes chance of viral escape
  • Independent mechanism of action makes shRNA complementary to other drugs

Pipeline

SomaGenics has discovery-phase programs in psoriasis and HIV.

References:

  1. Wang, C. H. Contag, H. Ilves, B. H. Johnston, and R. L. Kaspar,  Small hairpin RNAs efficiently inhibit hepatitis C IRES-mediated gene expression in human tissue culture cells and a mouse model. Mol. Therapy, 12:562-8 (2005). PMID 15953767
  2. H. Ilves, R. L. Kaspar, Q. Wang, A. A. Seyhan, A. V. Vlassov, C. H. Contag, D. Leake, and B. H. Johnston (2006) Inhibition of hepatitis C IRES-mediated gene expression by small hairpin RNAs in human hepatocytes and mice. Ann. N.Y. Acad. Sci., 1082: 52-55. PMID 17145925
  3. A.V. Vlassov, B. Korba, K. Farrar, S. Mukerjee, A. A. Seyhan, H. Ilves, R. Kaspar, S. A. Kazakov, and B. H. Johnston (2007) shRNAs targeting hepatitis C: effects of sequence and structural features, and comparison with siRNA. Oligonucleotides 17:223-236. PMID 17638526
  4. A. A. Seyhan, B. N. Alizadeh and B. H. Johnston (2007) RNA interference-mediated inhibition of Semliki Forest virus replication in mammalian cells.  Oligonucleotides 17(4): 473-84. PMID 18095875
  5. Ge Q., Dallas A., Ilves H., Shorenstein J., Behlke M.A., Johnston B.H. (2009) Effects of chemical modification on the potency, serum stability, and immunostimulatory properties of short shRNAs. RNA 16(1):118-30 (Epub Nov 30, 2009). PMID 19948766
  6. Ge Q., Ilves H., Dallas A., Kumar P., Shorenstein J., Kazakov S.A., and Johnston B.H. (2009) Minimal-length short hairpin RNAs: The relationship of structure and RNAi activity. RNA 16(1):106-17 (Epub Dec. 1, 2009). PMID 19952116