ISIS-ANGPTL3-L
Rx
, ISIS-APO(a)-L
Rx
, ISIS-APOCIII-L
Rx
, ISIS-GHR-L
Rx
, ISIS-GSK4-L
Rx
, ISIS-GSK6-L
Rx
,
and ISIS-TMPRSS6-L
Rx
. All of these drugs are designed to inhibit targets in the liver. We expect that some of
our future drugs, including our generation 2.5 drugs, could also be enhanced with our LICA technology.
OtherAntisense Targets andMechanisms
There are more than a dozen antisense mechanisms that can be exploited with our antisense technology.
While the majority of the drugs in our pipeline bind to mRNAs and inhibit the production of disease-causing
proteins through the RNase Hmechanism, we believe that our antisense technology is broadly applicable to
many different antisense mechanisms, including RNA interference, or RNAi, and splicing, and many different
RNA targets, including long, non-coding RNAs and toxic RNAs. For example, RNAi is an antisense mechanism
that uses small interfering RNA, or siRNA, that exploits a cellular protein complex called the RNA-induced
silencing complex, or RISC, to bind to the mRNAand to prevent the production of a disease-causing protein.
Most companies approach siRNAusing double-stranded oligonucleotides, which, due to their properties, require
complex formulations or drug delivery vehicles to achieve delivery to the cell. We have created single-stranded
RNAi compounds that, when we administer systemically, distribute in a manner similar to our second-generation
RNase H antisense drugs, without requiring the complex formulation or delivery vehicle typically necessary for
double-stranded RNAi oligonucleotides. These new single-stranded RNAi drug designs are an exciting
advancement in RNAi technology. In 2012, we published two papers in the journal Cell demonstrating that
single-stranded RNAi drugs distributed broadly, activated the RNAi pathway and reduced expression of targeted
genes in animal models. These data provide compelling evidence that single-stranded oligonucleotides can be
designed to exploit the RNAi pathway and silence gene expression of specific mRNAs in target tissues.
In addition, the diversity of our technology provides us with the potential to utilize many different antisense
mechanisms, like alternative splicing. Because splicing occurs at the RNA level, we can utilize our technology to
direct splicing to produce a particular protein product. For example, SMA is a splicing disorder caused by a loss
of, or defect in, the SMN1 gene leading to a decrease in the protein SMN. SMN is critical to the health and
survival of nerve cells in the spinal cord that are responsible for neuro-muscular growth and function. We
designed our ISIS-SMN
Rx
drug to alter the splicing of a similar gene, SMN2, to increase production of a fully
functional SMN protein. In 2014, we reported encouraging data on ISIS-SMN
Rx
in both infants and children with
SMA. ISIS-SMN
Rx
is currently being evaluated in two Phase 3 studies in infants and children with SMA. There
are a number of diseases, including cystic fibrosis and Duchenne muscular dystrophy, which scientists believe are
splicing disorders. These are diseases we could potentially treat using antisense modulation of splicing.
Because there are many different types of RNA that exist within the body, our antisense technology is not
limited to RNA sequences that translate into proteins, but rather we believe that we can apply the principles of
our technology to develop drugs that target other non-coding RNAs, such as toxic RNAs. For example, DM1 is a
form of muscular dystrophy that is caused by an abnormally long, toxic RNA that accumulates in cells and
prevents the production of proteins essential for normal cellular function. We designed our drug,
ISIS-DMPK-2.5
Rx
, to target and reduce the toxic RNA. In our preclinical studies, we observed effective
reductions of the toxic RNA that led to a reversal of disease symptoms that was sustained for up to one year in a
mouse model of disease. In December 2014, we initiated a clinical study evaluating ISIS-DMPK-2.5
Rx
in patients
with DM1.
Another RNA target for our antisense technology is microRNAs. To date, scientists have identified more
than 700 microRNAs in the human genome, and have shown that the absence or presence of specific microRNAs
in various cells is associated with specific human diseases, including cancer, viral infection, metabolic disorders
and inflammatory disease. To fully exploit the therapeutic opportunities of targeting microRNAs, we and
AlnylamPharmaceuticals, Inc. established Regulus as a company focused on the discovery, development and
commercialization of microRNA-based therapeutics. In 2014, Regulus reported human proof-of-concept with
RG-101 in HCV patients demonstrating that treatment with a single subcutaneous dose of RG-101 as a single
agent resulted in significant and sustained reductions in HCVRNA in a varied group of patients, including
difficult to treat genotypes and patients.
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