Gene Therapy Reverses Alzheimer's in Mice

Inder Verma, professor in the laboratory for genetics at the Salk Institute for Biological Studies (La Jolla, CA, USA).

The study's findings, which are the result of a close collaboration between researchers at the Salk Institute and scientists at the University of California in San Diego (UCSD; USA), are published in an on-line publication of the journal Nature Neuroscience.

Gene therapy in the past has been mostly used to transport normal genes into cells to compensate for faulty versions of the gene causing disease. In their study, the researchers utilized gene therapy to silence a normally functioning gene. Exploiting a process called RNA interference, they were able to inactivate the gene that helps produce the amyloid plaques that are one of the characteristics of AD.

"Within a month of treatment, mice that had already suffered memory deficits could learn and remember how to find their way through a water maze,” noted co-author Robert Marr, a post-doctoral researcher in Dr. Verma's lab.

"It appears that these mice can come back from a very severe level of disease progression,” added first author Dr. Oded Singer, also at the Salk. "This is a very important finding because humans are usually diagnosed when the disease has already progressed relatively far.” However, he cautioned that it is too early to make direct comparisons with the human disease because mice ordinarily do not develop the symptoms of the disease unless they are genetically modified to do so.

Amyloid plaques, which are insoluble protein tangles in the brain, can precede the onset of dementia by many years. These plaques are formed when enzymes cleave the amyloid precursor protein (APP), releasing the toxic beta amyloid fragments that bind together to form the sticky plaques. One of the enzymes doing the cleaving is called beta secretase or BACE1. Although the production of beta amyloid occurs in all brains, healthy brains are able to clear away excess amounts. Brains of people with AD, however, are incapable of controlling the buildup of beta amyloid.

Pharmaceutical companies for quite some time have been trying to find a drug that inhibits BACE1. Up to now, the objective has remained elusive. Instead of looking for chemical substances to inhibit BACE1, Dr. Singer, collaborating with the laboratories of the Salk Institute and lead author Eliezer Masliah from UCSD, utilized small biologic molecules, called short interfering RNA (siRNA), which disrupt the process of translating genes into proteins. They function similar to a dimmer switch, reducing the amount of available gene product, in this instance, the enzyme BACE1.

A modified lentivirus, which has been developed in Dr. Verma's lab, introduced the siRNAs into the brain cells of the transgenic mice that were producing huge amounts of human beta-amyloid and whose brains were full of plaques. "When you compare the brains of treated and untreated mice, the difference is striking. Silencing BACE1 reduced the number and size of plaques by two-thirds within a month, which is incredibly fast,” stated Dr. Singer.



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