Biomedical Engineering Reference
In-Depth Information
l
Once a carrier is approved for siRNA delivery, different mutant-specific siRNAs can be
formulated without changing the carrier system [5] .
l
Cancer-like diseases are highly patient specific. Thus, siRNA can be explored as personal-
ized therapy to benefit an individual patient [5] .
l
Antisense drugs have the potential to act as a chemosensitizing agent and can prevent mul-
tidrug resistance by blocking the resistance-causing component [9] .
7.11 Regulatory Aspects and Guidelines for Targeted
siRNA Delivery
After three decades of antisense research, to date only two antisense agents have been
approved by regulatory bodies, that too for local application only. However, a large
number of diseases require systemic administration for the desired application. Intense
research is in progress to make these agents available in the market for systemic use.
Leaders of antisense technology can learn from the reasons for unsuccessful entry into
clinics and the drawbacks of products like AEG35156, Bevasiranib, and AGN-749.
Despite these ups and downs, more than 13 siRNA products, 47 AS ODNs, 3 ribo-
zymes, and 9 aptamers have gained entry into clinical studies, and some others are
still at the preclinical stage. Although FDA has not yet issued any guidelines for the
targeted delivery of siRNA, several pharmaceutical and biotechnology-based compa-
nies involved in developing siRNA delivery techniques have laid down some internal
specifications for maximizing the reliable guidelines for validated design, process, and
evaluation of siRNA formulations [127,260] . Presented here are some rules and con-
ventions based on the practical understanding of siRNA design and delivery perfor-
mance. They should be followed while developing antisense formulations in order to
achieve regulatory approval and gain entry to the antisense therapeutic market.
1.   Determine a Rational Design of siRNA to Get the Right  
Strand into RISC
At present, many computer software programs with optimum selection rules are
available for specific siRNA designs. siRNA should be designed with excellent spec-
ificity to target mRNA with required chemical stability and pharmacologic effec-
tiveness. Rational siRNA design schemes are being developed that are based on an
understanding of RNAi biochemistry and on naturally occurring miRNA function.
The difference in thermodynamic stability of two strands of siRNA can determine
which strand will be directed towards RISC. This is taken into consideration while
designing siRNA.
2.  A Pool of Alleles Is Better Than a Single One
Several siRNAs or shRNAs should give the same phenotypic outcome, but similar
off-target effects can be achieved with a pool of different triggers. It is critical to
correlate this phenotypic outcome with the effectiveness of suppression. Examining
target protein levels will help determine the effective siRNAs out of the pool of
Search WWH ::




Custom Search