The Promise of Epigenetic Brain Control

[Biotech company Alnylam is] working with a medical device maker, Medtronic, on a way to deliver RNAi [RNA interference] treatment directly to the brain.... RNAi therapy involves researchers producing snippets of RNA, a close relative of DNA, that match a portion of a gene of interest. When administered, this so-called small interfering RNA (siRNA) causes the destruction of that gene's products before it can be turned into a protein. The specificity of RNAi for targeting particular genes has attracted a lot of interest from people who want to use it as a clinical treatment. _Technology Review

Alnylam wants to use RNAi to alter gene expression in Huntington's Disease and other neurodegenerative conditions of the brain.

Technology Review

RNAi control of gene expression is safer than some other forms of genetic therapy, in that the effect of RNAi is temporary -- self-limited. But that means that the therapeutic agent must be introduced repeatedly for the therapeutic effect to continue.

...a recurring challenge for the therapeutic RNAi field is how to deliver the siRNAs to the right place in the body. On their own, the small molecules do not survive long in the bloodstream, so simply injecting a patient with a solution of unprotected siRNAs is not effective. "The key technical hurdle is getting the siRNA [inside] the right cells," says Greene.

For several of its projects, Alnylam uses nanoparticles to protect and deliver its siRNAs, which can then be delivered by injection. But for genetic diseases that originate in the brain, the body's own defenses, namely the blood-brain barrier, complicate delivery further. To circumvent the blood-brain barrier, which prevents most molecules from leaving the bloodstream and entering the brain, Alnylam has looked to a different delivery mechanism: direct dosing of unpackaged siRNAs.

Medtronic, a Minneapolis company that designs and manufactures medical devices, has devised a way to allow this. Together, the companies have developed a treatment that combines Alnylam's RNAi therapeutic with Medtronic's drug delivery technology to treat Huntington's.

Huntington's, for which there is no cure, is caused by the loss of neurons due to a toxic protein made by a tainted gene. The idea behind the new treatment is to stop at least some of that protein's production so that it cannot damage the brain.

The treatment would use a device made by Medtronic that is already implanted in more than 250,000 patients to treat chronic pain and spasticity. The device features a catheter connected to a drug pump that's surgically implanted into the abdomen. The pump pushes drugs through the device and into the fluid around the spinal cord. In the case of the Huntington's RNAi work, the system is adapted to deliver liquids directly into the brain tissue. _Technology Review

In one way, this is a cautious approach to control of gene expression. But constant infusion of a therapeutic agent directly into the brain is both risky and expensive. Only the risk of a deadly disease such as Huntington's could justify that level of invasiveness.

A more ideal method of correcting genetic defects in brain tissue might be the introduction of engineered stem cells which will deliver the therapeutic agent continuously without the need for invasive hardware devices.

Even more ideal would be the permanent genetic alteration of the faulty brain cells which produce the faulty protein. But it will take more time to develop a safe way of doing that.

Our brains make us who we are. In Huntington's, victims of their own genes lose themselves in a one-way slide to a dark oblivion.

Genetic and epigenetic control of the brain will make a big difference. You might even call it a disruptive technology.