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Allies against autism
TRUMBULL, Conn.—Aimed ultimately at reversing the most physically disabling of the autism spectrum disorders, the Rett Syndrome Research Trust, a 501c3 nonprofit, has joined forces with Exton, Pa.-based Melior Discovery Inc. to screen drug candidates and eventually develop effective therapies.
"This partnership is further illustration of Melior's truly unique capabilities and competence in high-throughput, in vivo pharmacology," says Andrew Reaume, president and CEO of Melior Discovery.
In 2007, the journal Science published the work of chemist/researcher Adrian Bird, demonstrating the reversal of Rett Syndrome in mature mouse models with late-stage disease. Only days away from death, these animals recovered normal function and became indistinguishable from healthy mice in a matter of weeks. This singular achievement has catapulted Rett into new realms of possibility and positions Rett Syndrome to be the first curable childhood neurological disorder.
"We are pleased to be working with Melior and have been impressed with their ability to rapidly and effectively evaluate compounds in animal models. We look forward to our collaboration as we strive to identify compounds to ameliorate the devastating symptoms of Rett," says Monica Coenraads, executive director of the Rett Syndrome Research Trust.
Unlike Asperger's and other disorders on the spectrum, Rett Syndrome primarily strikes young girls just after they have learned to walk and say a few words—and then begins to drag their development backward. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Most live into adulthood and require total, around-the-clock care.
The disorder is caused by alterations of an X-linked gene, MECP2. The animal models that have been developed mimic the disorder well and provide an excellent system to test potential drug candidates.
"Alterations in this gene are also known to cause disorders beyond Rett including autism, childhood onset schizophrenia, learning disabilities and anxiety disorders," Coenraads tells ddn. "Classic Rett Syndrome is thought to affect one in 10,000 females. The prevalence of Rett is similar to ALS and Huntington's disease, while the prevalence of other MECP2 disorders beyond Rett is unknown. Furthermore, the MECP2 Duplication Syndrome has been recently identified, to date, mostly in males."
Rett Syndrome "affects every system in the body, and its symptoms are severe and debilitating," says Coenraads, mother to 13-year-old Chelsea, who was diagnosed with Rett Syndrome at age two. "Surprisingly, the symptoms have been dramatically reversed in preclinical models."
The unexpected reversal of Rett Syndrome in animal trials "presents us with the urgent challenge of determining whether such results can be achieved in human sufferers of Rett Syndrome," Coenraads says. "The neurobiology of Rett Syndrome is proving to be complex and the function of the MeCP2 protein remains elusive. Basic scientists around the world remain focused on these issues."
As this work progresses, there are clear approaches for intervention that must be pursued in parallel to understanding the function of MECP2, she said. RSRT has identified three such approaches: increasing levels of MeCP2 protein; identifying modifier genes; and taking a molecular target "independent" approach that focuses on functional improvement. The trust has embarked upon projects in each of the following categories.
"Our collaboration with Melior focuses on the third approach—the screening of approved drugs and compounds to seek functional improvement in any of the debilitating symptoms," Coenraads says. "This approach is a non-hypothesis driven approach, and in that respect, is complimentary to the first two approaches."
The partnership came about after RSRT and Melior were introduced by renowned medicinal chemist Christopher Lipinski, who serves as an advisor to both organizations. Lipinski is best known for the Lipinski Rule of 5, which has become a critical filter for drug development programs.
The Melior strategy takes an opportunistic view of identifying therapeutic potential with existing drugs where the science has not yet advanced enough to show us how it is that a given compound would be beneficial in this complex disease, Coenraads says. Melior has established numerous examples of identifying otherwise unpredicted therapeutic potential in well-characterized compounds with well-characterized targets and mechanisms of action, she said. In the majority of these instances, the new therapeutic potential was an on-target effect driven by the molecular target for which the compound was intended to emulate.
"This last point underscores that there is a significant amount of information missing from our collective knowledgebase and that the Melior approach can bypass these limitations," Coenraads says.
Melior has established a platform to allow for efficient and effective screening of existing drugs and compounds, and RSRT is eager to leverage this know-how for the identification of drugs/compounds that can alleviate symptoms, she says. Melior will also accept drugs/compounds from both academia and industry that have candidates they wish to test in the Rett animal model.
The ultimate goal of the partnership is to treat a broad spectrum of symptoms via drugs/compounds that were identified using Melior's approach, she says. Unfortunately, MECP2 mutations are sporadic and there is no at-risk population. It is therefore unlikely that the disorder will be eradicated.
"I am hopeful that a cure for Rett Syndrome is in our future," Coenraads says. "Unlike many disorders, Rett Syndrome has a gene, excellent animal models, the prospect of reversibility and a cadre of accomplished scientists. However, I recognize that developing a cure will entail an aggressive and unrelenting effort both in terms of the science and amassing the financial resources that will be required to sustain that effort. We now need an army of informed and committed supporters to help us see the damage of Rett Syndrome reversed not in mice, but in humans."