The goal of antisense therapeutics is to inhibit the gene expression of a protein. We can hope that someday the expression of the mutant huntingtin protein can be inhibited without inhibiting the wild (not expanded) huntingtin. Just what approach will achieve this is presently unknown and the subject of research. The following article is encouraging. --Jerry 09/01/98
Nature Biotechnology. 09/01/98

Getting antisense therapeutics into disease tissues can be a pain in the neck. A new approach using cellular transporter peptides linked to peptide nucleic acids (PNAs) may provide a solution, researchers report in Nature Biotechnology.

Getting antisense therapeutics into disease tissues can be a pain in the neck. A new approach using cellular transporter peptides linked to peptide nucleic acids (PNAs) may provide a solution. Researchers have obtained a significantly greater inhibiti on of the galanin pain receptor expression using PNA--transporter constructs than PNAs alone. They go on to demonstrate that these PNA constructs are effective in suppressing galanin receptor expression in the spinal cord, modifying pain responses in rats .

Antisense therapeutics---nucleic acids that bind and inhibit complementary mRNA sequences that encode faulty disease proteins---have traditionally been hampered by their poor stability and availability to diseased tissues in the body. A new type of nucleic acid, PNA, in which the sugar phosphate backbone has been replaced with peptide groups, allows the design of antisense agents that are much more stable in the bloodstream. The problem has been getting these PNAs into the body's diseased cells.

Two naturally occurring peptides---transportan and penetratin---shuttle proteins across the cellular membrane, a property Ulo Langel and colleagues exploited to enhance the penetration of cells by PNA directed against the galanin receptor. Compared with unmodified PNAs, these constructs were much more efficient at lowering the levels of galanin receptor both in intact cells and in an animal model. What's more, administration of the hybrid PNA molecules to rats resulted not only in a decrease in the levels of the receptor, but a decrease in an electrophysiologic response (a measure of pain). As antisense therapeutics can be targeted to virtually any cellular messenger RNA, this delivery approach promises to open up therapeutic avenues to a variety of diseases as well as allowing researchers to dissect complex metabolic pathways in living model systems.