Anion Transport


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Anion Transport

Anion Transport

Lead Inventor: Konstantin Petrukhin Ph.D.

Problem or Unmet Need:
Retinal detachment (RD) has a lifetime risk of 1 in 300 people and may lead to blindness if left untreated. The mainstay therapy for RD is surgical intervention with pneumatic retinopexy, scleral buckling techniques or vitrectomy to repair the tear and reattach the retina. In other cases, where RD is due to exudative fluid and edema/gliosis, treatment involves procedures such as thermotherapy and cryotherapy to reattach the retina as well as intravitreal injection of steroids to limit inflammation and edema. Surgical therapy for RD is invasive and has a modest success rate of 60-95% and steroid injections are of limited long-term efficacy. There is no current therapy with the combined benefits of being non-invasive and efficacious in the long-term to treat RD. Dr. Petrukhin has developed a unique technology that encompasses both of these properties in the form of a small molecule drug that has durable efficacy in minimizing inflammation and gliosis as well as stimulates the removal of exudative fluid.

Details of the Invention:
In RD, when the neural retina separates from the retinal pigment epithelium (RPE), there is concomitant cellular inflammation and edema/gliosis which results in fluid leaking between the two spaces. Dr. Petrukhin's drug is designed to manipulate fluid transport across membranes by inhibition of anion transport channels and it can be administered via intravitreal injection directly to the RPE. The drug facilitates the removal of fluid from the space between the nueral retina and RPE while simultaneously downregulating inflammatory processes that lead to the gliosis seen in RD.

Applications:

  • Primary treatment of retinal detachment related to exudative fluid
  • Adjunctive therapy for retinal detachment treated by surgery
  • Primary treatment for gliosis in macular degeneration and retinitis pigmentosa
  • Primary treatment for inflammation and exudative fluid in choroidal tumors


Advantages:
  • Easily delivered via intravitreal injection
  • Acts locally thereby minimizing systemic side effects
  • Durable efficacy in minimizing gliosis already proven in clinical trials for other neurological conditions
  • Mechanism of action to facilitate fluid removal (manipulation of anion transport) is effective and well established
  • May prevent the need for more invasive procedures (scleral buckling surgery, cryotherapy, thermotherapy)

Patent Status: Patent Pending

Licensing Status: Available for Licensing and Sponsored Research Support

Publications: Petrukhin K. New therapeutic targets in age-related macular degeneration. Expert Opin Ther Targets 11(5):625-39. 2007

Further Information
Donna See
Email: TechTransfer@columbia.edu

Abstract

Pendrin and prestin both belong to a distinct anion transporter family called solute carrier protein 26A, or SLC26A. Pendrin (SLC26A4) is a chloride-iodide transporter that is found at the luminal membrane of follicular cells in the thyroid gland as well as in the endolymphatic duct and sac of the inner ear, whereas prestin (SLC26A5) is expressed in the plasma membrane of cochlear outer hair cells and functions as a unique voltage-dependent motor. We recently identified a motif that is critical for the motor function of prestin. We questioned whether it was possible to create a chimeric pendrin protein with motor capability by integrating this motility motif from prestin. The chimeric pendrin was constructed by substituting residues 160–179 in human pendrin with residues 156–169 from gerbil prestin. Non-linear capacitance and somatic motility, two hallmarks representing prestin function, were measured from chimeric pendrin-transfected human embryonic kidney 293 cells using the voltage clamp technique and photodiode-based displacement measurement system. We showed that this 14-amino acid substitution from prestin was able to confer pendrin with voltage-dependent motor capability despite the amino acid sequence disparity between pendrin and prestin. The molecular mechanism that facilitates motor function appeared to be the same as prestin because the motor activity depended on the concentration of intracellular chloride and was blocked by salicylate treatment. Radioisotope-labeled formate uptake measurements showed that the chimeric pendrin protein retained the capability to transport formate, suggesting that the gain of motor function was not at the expense of its inherent transport capability. Thus, the engineered pendrin was capable of both transporting anions and generating force.