Taking down Down syndrome

NUTLEY, N.J.—Scientists from Roche, the University ofCantabria and Spain's Cajal Institute have published their findings on recentwork with Down syndrome that highlights a potential new approach to combat thecognitive damage caused by the genetic condition. Through the use of aninvestigational compound, the researchers were able to selectively blockspecific receptors in the brain, and by so doing, reverse neurological deficitsin a mouse model of Down syndrome.

The compound in question, RO4938581, is selective for brainreceptors that contain the GABA-a5 receptorsubunit. When administered, the compound proved to be capable of correctingcognitive and behavioral deficits in Ts56Dn mice, as well as improvingabnormalities of nerve cell number and function in adult Ts65Dn mouse brains.As an additional benefit, the improvement occurred without unwanted sideeffects that have historically hindered the use of non-selective GABA-Areceptor blockers.

"These preclinical results suggest that GABA-a5 receptors can be targeted for thetreatment of cognitive impairment in individuals with Down syndrome resulting,at least in part, by exaggerated inhibition of neural circuits,"Maria-Clemencia Hernandez, senior scientist at Roche and lead author on thepaper, said in a press release.

The compound's effects are particularly encouraging giventhe difficulty of balancing the inhibition of GABA. If it is entirelyinhibited, Hernandez says, there are detrimental side effects such as seizuresand panic attacks, among others. But through the modulation and reduction ofactivity the investigational compound manages, the side effects are notexperienced. In addition, she notes, it "seems to be very safe."

"What is expected is that the longer the treatment is, themore likelihood that we will see better improvement," says Hernandez.

As for whether there is potential for this compound toprevent cognitive impairment if it is administered early in life in childrenwith Down syndrome, Hernandez says that is what the team hopes for. Should theresults seen in the animal models reflect the efficacy in humans, she says, itcould be expected that there would be a higher benefit if administered duringformative years "because it's the time when we are more actively learning newthings, and it will help in the end to have better quality of life, learn morethings, being able to be more independent later on in life."

The Global Down Syndrome Foundation notes that Down syndromeis "the least funded major genetic condition" by the National Institutes ofHealth, and as such, few corrective options exist. The need for such options issignificant, however, as the National Down Syndrome Society estimates that onein every 691 babies in the United States are born with Down syndrome, while theWorld Health Organization approximates that the global incidence is between onein 1,000 to one in 1,100 live births, noting that "approximately 3,000 to 5,000children are born with this chromosome disorder" every year.

A related compound—RG1662, a Roche GABA-a5 Negative Allosteric Modulator (NAM)—iscurrently under investigation for cognitive enhancement in Down syndromepatients. The compound acts on a subset of receptors for GABA found in discretebrain regions associated with cognitive processing, where they hindercommunication between nerve cells. GABA-a5NAMs suppress GABA's action, limiting the inhibiting signals between nervecells. The compound is the first specifically designed to ameliorate thecognitive impairment found in Down syndrome, and by targeting GABA-a5 receptor subtypes, RG 1662 is capable oftargeting GABA over-activity in brain systems that are critical for learning,cognition and memory.

In previous tests, the GABA-a5NAM has been shown to be well tolerated in healthy volunteers, and Rochecurrently has a trio of early-phase clinical trials underway in Down syndrome.The trials include a study to evaluate the safety and tolerability of theinvestigational molecule, a non-drug study to evaluate cognition and adaptivebehavior in adolescents and young adults and an imaging (PET) study todetermine receptor expression and occupancy by the investigational molecule.Roche expects the Phase I studies to be complete this year.

"Our drug research in Down syndrome may offer a noveltherapeutic avenue to treat the cognitive deficits in people with Downsyndrome, enhance their communication skills and ultimately help them havegreater independence in their daily lives," Luca Santarelli, head ofNeuroscience at Roche, commented in a statement. "The development of this agentis in line with our strategy to discover new medicines that are based on a deepunderstanding of disease mechanisms and provide options for conditions of highunmet medical need."

Thepaper, "Reducing GABA-a5 receptor-mediated inhibition rescues functional andneuromorphological deficits in a mouse model of Down syndrome," appeared in theJournal of Neuroscience Feb. 27.