Novel PDE4 Inhibitor Improves Symptoms of Autism Disorder Fragile X Syndrome in Animal Model Interview with:

Dr. Mark E. Gurney, PhD MBA

Dr. Gurney

Dr. Mark E. Gurney, PhD MBA
Chairman & CEO, Tetra Discovery Partners Inc. What is the background for this study? What are the main findings?

Response: Fragile X is a genetic condition. Affected patients display a range of behavioral and other symptoms, including seizures, sleep disorders, anxiety, irritability, hyperactivity, autism, mild-to-severe cognitive impairment and intellectual disability.

BPN14770 is a novel therapeutic agent that selectively inhibits phosphodiesterase-4D (PDE4D). Inhibition of PDE4 has been validated as a treatment strategy by many research groups in the Fragile X field, but non-selective PDE4 inhibitors have been associated with significant GI side-effects that have limited those drugs’ use. As a selective inhibitor, such side-effects were not seen for BPN14770 in a Phase 1 clinical trial in healthy young and elderly adults.

In the current study, daily treatment of Fragile X knock-out (FXS) mice with BPN14770 showed a reduction in hyperarousal, improved social interactions and natural behaviors, and changes in nerve structure in the prefrontal cortex of the brain, the portion of that brain associated with cognition. Moreover, the drug’s benefit persisted for two weeks after all drug was cleared from the mice. At the same time, the behavior of normal mice treated with the drug remained unchanged. Examination of neurons from the prefrontal cortex of the treated FXS mice showed an improvement in dendritic spine morphology.

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FDA Advisory Committee Recommended Approval of First Gene Therapy For Inherited Eye Disease Interview with:
Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting BlindnessDr. Stephen M. Rose, PhD
Chief Research Officer
Foundation Fighting Blindness

Dr. Rose discusses the FDA advisory panel unanimously recommended approval of Spark Therapeutics’ Gene Therapy Luxturna  for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal dystrophies, a group of rare blinding conditions caused by one of more than 220 different genes. Would you tell us a little about IRD? Whom does it affect and how?  How common is this disorder?

Response: The retina at the back of the eye is responsible for collecting light and turning it into signals that are transmitted to the brain and interpreted as vision. Think of the retina as the film in a camera, or more recently the sensor at the back of a digital camera. Inherited rare retinal degenerations are when the retina at the back of the eye deteriorates and loses its ability to capture light, thereby leading to blindness.

iRDs can affect anyone, no matter race or ethnicity. These are inherited conditions that are passed down from parents to children, if a parent or both parents are either affected already or are carriers for a variant in any of the over 250 genes responsible for retinal degeneration.

There are over 15 different types of iRDs, with retinitis pigmentosa being the most common with a US affected population around 100,000. The rest of the iRDs make up another approximately 100,000 affected individuals in the US, so there are about 200,000 total affected individuals in the US. Worldwide these iRDs affect somewhere around one to two million individuals.

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Vasopressin-Inhibitor Tolvaptan Reduces Kidney Function Decline in Polycystic Kidney Disease Interview with:
Dr. TorresVicente E. Torres, M.D., Ph.D.

Director of the Mayo Clinic Translational Polycystic Kidney Disease (PKD) Center What is the background for this study? What are the main findings?

Response: Experimental work pioneered by Dr. Jared Grantham showed that cyclic AMP, an intracellular signaling molecule, promotes the development and growth of cysts. Vasopressin, a hormone produced by the pituitary gland, stimulates the production of cyclic AMP in the collecting ducts, from which most cysts derive in autosomal dominant polycystic kidney disease (ADPKD). While this effect of vasopressin is necessary for the kidneys to concentrate and reduce the volume of urine, it promotes the development and growth of cysts in patients with ADPKD. Dr. Vincent Gattone realized that inhibiting the action of vasopressin could be protective in polycystic kidney disease. Work in our and other laboratories confirmed that suppression of vasopressin production, release or action reduces cyst burden, protects kidney function, and prolongs survival in rodent models of the disease.

This experimental work provided a strong rationale for clinical trials of tolvaptan, a vasopressin V2 receptor antagonist. Tolvaptan reduced the rate of kidney growth in the TEMPO 3:4 trial, in patients with early ADPKD. It also reduced the rate of decline in kidney function, measured by the estimated glomerular filtration rate (eGFR), from 10.1 to 6.8 mL/min/1.73 m2 over three years. The eGFR benefit was maintained during two additional years when all the patients were treated with tolvaptan in an open label extension of the TEMPO 3:4 trial (TEMPO 4:4). Safety laboratory tests performed every four months showed elevations of liver transaminases in blood in 4.4% of tolvaptan and 1% of placebo-treated patients. Three of 1,271 tolvaptan-treated patients during TEMPO 3:4 and TEMPO 4:4 had evidence of potentially serious drug-induced liver injury. These abnormalities occurred all within the first 18 months of exposure to tolvaptan.

Based on the TEMPO 3:4 results, tolvaptan was approved for the treatment of rapidly progressive ADPKD in Japan, Canada, European Union, Switzerland and South Korea. In the United States, the Food and Drug Administration requested additional data to further evaluate the efficacy and safety of this drug. The REPRISE trial was performed to determine the efficacy and safety of tolvaptan in patients with later stage ADPKD.

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