Tetra is developing a platform of drug products to treat cognitive impairment. Cognitive impairment occurs when synapses within the brain do not communicate properly at a cellular level. Cognitive problems occur when there is too much activity, or not enough—when neurons do not signal properly. Within brain cells, the substance which controls the way synapses communicate is cyclic AMP, or cAMP.
Tetra’s science builds on previous work by Nobel laureates that identified PDE4 (Phosphodiesterase 4) as a key enzyme that shapes proper cAMP signaling. Specifically, PDE4 limits the spread of cAMP so that spatial and temporal patterning of information is maintained.
The chemistry is a bit complicated. It turns out that PDE4 has 4 subtypes, and drug-induced inhibition of one (or more) of these subtypes can produce nausea or vomiting. To address such undesirable side-effects, Tetra has taken a different approach. Our compound targets only one of the PDE4 enzyme subtypes, and only at specific times of cellular activity. Tetra’s compound is designed to modulate, rather than completely inhibit, PDE4D. The result is that Tetra’s drug improves cognitive function by prolonging cAMP activity. Safety and tolerability are improved because the enzyme is not completely inhibited.
Our lead drug targeting PDE4D, BPN14770, is being developed for treating cognitive impairment in Fragile X Syndrome and Alzheimer’s disease with potential applications for Huntington’s disease, schizophrenia, and major depression. Rather than addressing a specific chemical deficit or dysfunction in a specific neural circuit, targeting PDE4D has the potential to augment the fundamental processes underlying learning and memory in the human brain, thereby allowing compensatory brain mechanisms to improve function in the diseased brain.
SELECTED SCIENTIFIC PUBLICATIONS
- The Use of Facebook Advertising to Recruit Healthy Elderly People for a Clinical Trial: Baseline Metrics. Cowie JM, Gurney ME. JMIR Res Protoc. 2018 Jan 24;7(1):e20. doi: 10.2196/resprot.7918. PMID: 29367186
- Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D). Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Scientific Reports. 2017 Nov;7(14653).PMID: 29116166 doi: 10.1038/s41598-017-15028-x
- Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. Wilson NM, Gurney ME, Dietrich WD, Atkins CM. PLoS One. 2017 May 19;12(5):e0178013. doi: 10.1371/journal.pone.0178013. eCollection 2017. PMID: 28542295
- Chronic Cognitive Dysfunction after Traumatic Brain Injury is Improved with a Phosphodiesterase 4B Inhibitor. Titus DJ, Wilson NM, Freund JE, Carballosa MM, Sikah KE, Furones C, Dietrich WD, Gurney ME, Atkins CM. J Neurosci. 2016 Jul 6;36(27):7095-108. doi: 10.1523/JNEUROSCI.3212-15.2016. PMID: 27383587
- Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Gurney ME, D’Amato EC, Burgin AB. Neurotherapeutics. 2015 Jan;12(1):49-56. doi: 10.1007/s13311-014-0309-7. PMID: 25371167
- Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Hagen TJ, Mo X, Burgin AB, Fox D 3rd, Zhang Z, Gurney ME. Bioorg Med Chem Lett. 2014 Aug 15;24(16):4031-4. doi: 10.1016/j.bmcl.2014.06.002. Epub 2014 Jun 12. PMID: 24998378
- Structural basis for the design of selective phosphodiesterase 4B inhibitors. Fox D 3rd, Burgin AB, Gurney ME. Cell Signal. 2014 Mar;26(3):657-63. doi: 10.1016/j.cellsig.2013.12.003. Epub 2013 Dec 19. PMID: 24361374
- Small molecule allosteric modulators of phosphodiesterase 4. Gurney ME, Burgin AB, Magnusson OT, Stewart LJ. Handb Exp Pharmacol. 2011;(204):167-92. doi: 10.1007/978-3-642-17969-3_7. Review. PMID: 21695640
- Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME. Nat Biotechnol. 2010 Jan;28(1):63-70. doi: 10.1038/nbt.1598. Epub 2009 Dec 27. PMID: 20037581
MEDICINES FOR ALZHEIMER'S DISEASE | TETRA CO-INVESTIGATORS
NIH BLUEPRINT CONSULTANTS
|Vince Groppi, PhD / Pharmacology Lead||Donna Romero, PhD / Chemistry Lead|
|Marc Bailie, PhD / Safety and Toxicology Lead||Ron White, PhD / DMPK Lead|
|Jon Lawson, PhD / Process Chemistry||Jay Sisco, PhD / Formulation/Drug Product|
NIMH PET LIGAND CO-INVESTIGATORS
|Robert Innis MD PhD|
|Victor Pike PhD|
|Carlos Zarate MD|