CALIFIA BIO

Califia Bio was founded with the goal of our in-house research to be focused on addressing drug discovery for diseases of the central nervous system that are largely ignored by the pharmaceutical industry. One of the diseases we are interested in is Rett Syndrome.

Rett Syndrome (RTT) is an X-chromosome linked developmental disease, which manifests during the first 6 to 18 months of life in females; presumably the mutations are almost universally fatal in the development of males possessing only the single mutant X chromosome. The disease alters the development of the central nervous system and is caused by various mutations for a gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing. MeCP2 is likely an epigenetic factor required for neuronal terminal differentiation. Mutations in MeCP2 result in several neuropsychiatric and physical abnormalities. The abnormalities include deceleration of head growth, developmental stagnation, stereotypic hand wringing and behavioral features of autism. The disease causes breathing problems such as hyperventilation and breath holding/apneas. Most victims are eventually dependent on wheel chairs; as victims age they often exhibit Parkinson’s -like symptoms. (1)

There is a growing body of knowledge regarding the effects of MeCP2 mutations, however this knowledge is still imperfect. It is known that RTT brains show reduced neuronal growth and complexity and MeCP2 mutations likely inhibit dendritic branching. Although a number of therapies have been suggested to reduce or reverse the effects of of MeCP2 mutations, to date there is no viable therapy and there is no one obvious route to a molecular target. One of the targets of MeCP2 transcriptional control is the BDNF

gene. Brain Derived Neurotrophic Factor (BDNF) is a large protein synthesized in the brain and supports the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In animal studies over-expression of BDNF in certain regions of the brain, prevents dentritic atrophy induced by MeCP2 mutations.(2) It is impossible to administer a large protein into the brains of RTT patients, therefore one route of possible therapy involves designing small molecule mimetics of BDNF, capable of passing the blood brain barrier and which activate BDNF’s downstream signaling partners. This area of research also complements well with our interest in kinase signaling pathways that preserve or promote synaptodendritic complexity in therapy for HIV-associated neurological diseases.