Sepiapterin reductase inhibitors for the treatment of pain
Inventors: Clifford Woolf, Julian Blagg
Invention Types: Therapeutics
Research Areas: Neurology/Neuroscience
Keywords: Drug Discovery, Neuropathy, Pain, Small Molecule/DrugFor More Information Contact: Caron, Connie
Sepiapterin reductase (SPR) is part of the tetrahydrobiopterin (BH4) de novo synthesis cascade. Prior to joining Boston Children's, Drs. Clifford Woolf, Michael Costigan and Alban Latremoliere, using expression arrays had identified three of the enzymes that are crucial to the control of intracellular levels of BH4 as highly regulated within injured sensory neurons, including SPR. Up-regulation of these enzymes in these injured neurons causes a massive excess of BH4. This was validated in humans by identification of gene polymorphisms that reduce BH4 levels and showing that these are associated with a reduced risk of chronic pain.BH4 is an essential cofactor for the enzymes that produce serotonin, dopamine, epinephrine, nor-epinephrine and nitric oxide. Altering BH4 levels in injured sensory neurons consequently has profound effects on cellular physiology. Inhibiting SPR will reduce pathological BH4 levels in sensory neurons while retaining basal BH4 levels in other cells and therefore acts as an analgesic without adverse side effects. To achieve this goal, several compound classes of small molecule inhibitors of SPR were identified and are described and claimed in a patent application that is now assigned to Children's. Dr. Woolf's lab at Boston Children's is currently testing one series of compounds, including ACS 8099, in proof of concept in vivo studies for treatment of chronic pain.
The invention relates to a method of treating, reducing, or preventing chronic pain. Acute pain (normo-sensation and resolving inflammatory) is protective and is not altered by these treatments. Chronic pain may be neuropathic, inflammatory, or dysfunctional and is refractory to most existing analgesics. This treatment is targeted at chronic pain, especially neuropathic. The therapeutic goal is pharmacological restoration of normal BH4 levels in the somatosensory system.
• Currently, there is no safe or highly effective treatment for chronic pain
• Human validated novel target (first in class)
• Can measure biomarker BH4 reduction
• Not opioid, so non-addictive
• Likely few side effects
Sponsored Research or Licensing
Key Publications: Costigan M, Latremoliere A, Woolf CJ. Analgesia by inhibiting tetrahydrobiopterin synthesis. Curr Opin Pharmacol. 2012 Feb;12(1):92-9. Epub 2011 Dec 15. Review. PubMed PMID: 22178186; PubMed Central PMCID: PMC3288148.
Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, LÃ¶tsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269-77. Epub 2006 Oct 22. PubMed PMID: 17057711.
IPStatus: Pat. Pend.