Glaucoma is a progressive ocular syndrome characterized by degeneration of the optic nerve and irreversible visual field loss. Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Increased IOP is the result of an imbalance between synthesis and outflow of aqueous humor (AH). Blocking β2 adrenergic receptor (ADRB2) has shown to reduce IOP by decreasing production of AH at the ciliary body (CB). SYL040012 is a siRNA designed to specifically silence ADRB2 currently under development for glaucoma treatment. Here, we show that SYL040012 specifically reduces ADRB2 expression in cell cultures and eye tissues. The compound enters the eye shortly after administration in eye drops and is rapidly distributed among structures of the anterior segment of the eye. In addition, SYL040012 is actively taken up by cells of the CB but not by cells of systemic organs such as the lungs, where inhibition of ADRB2 could cause undesirable side effects. Moreover, SYL040012 reduces IOP in normotensive and hypertensive animal models and the effect appears to be long lasting and extremely well tolerated both locally and systemically.

RNA interference is an endogenous mechanism present in most eukaryotic cells that enables degradation of specific mRNAs. Pharmacological exploitation of this mechanism for therapeutic purposes attracted a whole amount of attention in its initial years, but was later hampered due to difficulties in delivery of the pharmacological agents to the appropriate organ or tissue. Advances in recent years have to a certain level started to address this specific issue. Genetic diseases are caused by aberrations in gene sequences or structure; these particular abnormalities are in theory easily addressable by RNAi therapeutics. Sequencing of the human genome has largely contributed to the identification of alterations responsible for genetic conditions, thus facilitating the design of compounds that can address these diseases. This review addresses the currently on-going programs with the aim of developing RNAi and other antisense compounds for the treatment of genetic conditions and the pros and cons that these products may encounter along the way. The authors have focused on those programs that have reached clinical trials or are very close to do so.

The central dogma of biology describes the transfer of biological information from DNA through to protein (1). In the first phase, known as transcription, DNA is converted into a complementary sequence of messenger RNA (mRNA). This mRNA allows the genetic message to be communicated outside of the cell nucleus, to other areas of the cell, where it is then translated into protein by ribosomes. Post-transcriptional regulatory events take place after an RNA molecule is formed; thereafter the resulting RNA molecule is decoded to produce a specific protein. Protein production depends on the length of survival of RNA in a cell and the efficiency of its utilizations.

The central dogma of biology describes the transfer of biological information from DNA through to protein (Crick, 1970). In the first phase, known as transcription, DNA is converted into a complementary sequence of messenger RNA (mRNA). This mRNA allows the genetic message to be communicated outside of the nucleus, to other areas of the cell, where it is then translated into protein by ribosomes. Most human diseases arise from increased function or dysfunction of proteins within the body. Since these proteins are generated from DNA via mRNA, modulation of this flow of genetic information can convey a therapeutic effect on the disease state. Mammalian cells possess the genetic instruction to make 50,000 to 100,000 different proteins but only 10-20% of these are found in any single cell. Therefore, a gene must contain instructions for the regulation of the production of protein in correct amounts and at the correct time for each cell type. Gene regulation is one of the most complex molecular processes known, involving up to 10% of the proteins that cells produce. In 1998, Andrew Fire and Craig Mello described RNAi as an endogenous gene expression pathway activated by double-stranded RNA (dsRNA) in the worm Caenorhabditis elegans. For this pioneering work, Fire and Mello were awarded the 2006 Nobel Prize in Physiology or Medicine. The discovery of the natural RNAi mechanism for sequence-specific gene silencing launched a new era in antisense technology. During the 1990s, a number of genesilencing phenomena that occurred at the posttranscriptional level were discovered in plants, fungi, animals and ciliates, introducing the concept of post-transcriptional gene silencing (PTGS) or RNA silencing (Baulcombe, 2000; Matzke et al., 2001). The most important technologies for gene suppression are: antisense oligonucleotides, aptamers, ribozymes and RNA interference (RNAi). The first report that gene expression could be modulated by the use of reverse complementary (antisense) oligonucleotides was made in 1978. Antisense molecules are synthetic segments of DNA or RNA, designed to mirror specific mRNA sequences and block protein production, these molecules are designed to inhibit translation of a target gene to protein via interaction with mRNA. Aptamers are single-strand DNA or RNA oligomers, which can bind to a given ligand with high affinity and specificity due to their particular 3-D structures and thereby antagonize the biologic function of the ligand. Recent developments demonstrate that aptamers are valuable tools for diagnostics, purification processes, target validation, drug discovery and therapeutics. Ribozymes are