As far as the Centers for Disease Control and Prevention is concerned - to say nothing of the mass media - the country is in the grip of an autism epidemic. According to data released earlier this year, one in 150 boys is now diagnosed with an autism spectrum disorder. In New Jersey, the state with the highest rate of diagnosis, the rate is around 1 percent. (See BioWorld Today, Feb. 21, 2007.)

That prevalance estimate is up tenfold from only a decade ago. And the drug industry, as well as its funders, still are catching up. "The risk-return profile [for drugs targeting autism spectrum disorders] is not what's typically funded by venture capitalists or public companies," Randy Carpenter told BioWorld Today.

Carpenter is co-founder and CEO of Cambridge, Mass.-based biotech firm Seaside Therapeutics, whose aim it is to "develop new treatments that are potentially disease-modifying for autism spectrum disorders." Seaside was founded a little more than two years ago as one of four successor companies to Sention Inc. The company's lead program, which is headed for an investigational new drug filing in 2008, wants to use metabotropic glutamate receptor antagonists to treat Fragile X syndrome.

Fragile X syndrome, whose symptoms include abnormalities in brain structure and connectivity that lead to impaired cognitive function, developmental delay, attention deficit and hyperactivity, anxiety, and obsessive-compulsive and autistic behavior, is definitely not in itself a blockbuster indication - it affects an estimated 90,000 Americans. But it is a leading cause of mental retardation, and the most common cause of autism in those cases where any cause can be established.

Carpenter said that the perception of autism as a niche market has been changing "dramatically" over the past few years, spurred by the increasing incidence estimates as well as last year's approval of Janssen's antipsychotic Risperdal for irritability in autistic patients.

But for now, the company has no traditional venture funding. Instead, it has grants from the National Institutes of health and National Institute of Mental Health totaling more than $3 million, as well as grants from the advocacy groups Autism Speaks and the Fragile X Research Foundation or Fraxa.

Seaside also has what venture philanthropy support - funding from a wealthy individual whose preferences led to the name Seaside Therapeutics. ("He gave us the money; he can pick the name," Carpenter said.) Carpenter estimates the company has enough money to last for three years.

Fragile X syndrome is a bit of a misnomer - in persons with the disease, the X chromosome is fragile "only under some very special conditions," investigator Mark Bear told BioWorld Today.

The underlying cellular problem is not a Fragile X chromosome, but a lack of Fragile X mental retardation protein or FMRP. That lack seems to cause problems by allowing the unchecked activation of class 1 metabotropic glutamate receptors, which Seaside is targeting.

In the Dec 20, 2007, issue of Neuron, senior author Bear, who is a professor of neuroscience at the Massachusetts Institute of Technology and co-founder of Seaside Therapeutics, and his colleagues provided experimental support for the idea that reducing mGluR5 activity is a way to treat the symptoms of Fragile X syndrome.

The team showed that in a mouse model, which lacks FMRP and also has reduced expression of mGluR5, several of the symptoms of Fragile X disease are reversed.

Metabotropic glutamate receptors "play different roles," Bear said, but one important role is that they appear to control the signals that lead to protein synthesis in the brain in response to brain activity, which gives them an important gatekeeper function in learning and memory. Lack of FMRP, the theory goes, removes a regulator of metabotropic glutamate receptors, leading to too much protein synthesis and an attendant miswiring of brain connections.

Bear and his team created a mouse that lacked FMRP and also lacked one copy of the gene for the major brain metabotropic glutamate receptor, mGluR5; the rationale was that because there was less receptor to go into overdrive, the consequences of not having FMRP should be attenuated by also reducing the levels of mGluR5.

The researchers tested several of the symptoms of Fragile X, and showed that in double mutant mice, the mGluR5 gene reduction greatly alleviated many abnormalities produced by loss of FMRP.

The double mutants showed a rescue of abnormalities in the structure of synaptic connections, brain protein synthesis, memory and body growth. The double mutants also had fewer epileptic seizures than the FMRP knockouts.

In contrast to the reversal of Fragile X symptoms in the brain, another symptom of Fragile X remained unaffected in the double mutants. They still had macroorchidism, or large testicles, which is among the physical abnormalities of male Fragile X sufferers.

Bear put that particular failure of the double mutant into context: "In a sense, it was a bit of a stretch to think that it would work," he said, because despite the many weary female jokes about what men think with, the testicles are not part of the nervous system. But because mGluR5 receptors are expressed in the testicles, there was some rationale to expect that macroorchidism would be affected by the double mutant.

Bear said that perhaps success would come with a mouse model that reduced expression of other type 1 metabotropic glutamate receptors.

In the meantime, the results give plenty of encouragement for the idea that Fragile X syndrome could be alleviated by metabotropic glutamate receptor blockers.

Carpenter also said the fact that Bear's lab used a genetic manipulation to reduce mGluR5 activity "makes us pretty convined that our compounds are working through the mechanism we propose," rather than through off-target effects on other receptors.