Potential PWS Treatments Currently in Development

These potential PWS treatments are in development as of July 2015:
Approach How it works Development Phase Investigators /Company   *= FPWR funded   Advantages   Potential Limitations
Genetic Therapies- These therapies seek to activate the PWS region genes on the silent maternal chromosome 15 OR provide critical missing genes OR provide a substitute function for PWS genes.  These are early stage projects - optimizing approaches and examining feasibility / efficacy in cell and animal models of PWS.
Gene activation – small molecules Drugs targeting enzymes that establish / maintain epigenetic marks, activating the PWS genes on the maternal chromosome 15 Discovery / Preclinical *Dr. Jiang Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms. Would be applicable to all subtypes of PWS (del, UPD, imprinting) Could activate other genes within or outside the PWS region; those consequences are not yet known. There may be critical “windows” in which therapy would be effective
TALE – based activation Delivery of a gene or protein that to specifically target and activate the PWS region on the normally silent maternal chromosome 15 Discovery *Dr. Segal Addresses the underlying cause of PWS, so has the potential to profoundly impact on symptoms. Applicable to all subtypes. Specificity may be better. Potential for 1x therapy Gene delivery likely to be challenging.   No FDA approved gene therapy treatment exists yet in US so steeper regulatory pathway is likely.  Potential for ‘off target’ effects. 
CRISPR-based activation Delivery of a specialized gene/protein to specifically target and activate the PWS region on the normally silent maternal chromosome 15 Discovery *Dr. Nicholls    *Dr. Lalande Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms. Applicable to all subtypes. Specificity may be better. Potential for 1x therapy. Gene delivery likely to be challenging.   No FDA approved gene therapy treatment exists yet in US so steeper regulatory pathway is likely. Potential for ‘off target’ effects
Oligonucleotide therapy Replacement of function of PWS region genes using small pieces DNA Preclinical *Dr. Stamm Addresses the underlying cause of PWS, so has the potential to profoundly impact symptoms. Dosage may be better titrated than other gene therapy approaches. Delivery may be more readily accomplished.  Need for repeat therapy.  Oligonucleotide must be brain penetrant and will probably need to target a large number of cells.  To date, efficacy of this approach in other diseases has been relatively poor. 
Hyperphagia / Obesity Drugs these drugs are being evaluated for their ability to curb appetite and/or induce weight loss in people with PWS
Beloranib Bypasses hypothalamus, affects metabolism and fat breakdown Phase 3 Zafgen Significant weight loss in general population.   Decreased hyperphagia in Phase 2 Good safety profile to date Not yet FDA approved.  Long term safety not yet known 
RM-493 Bypasses proposed POMC neuron defect Phase 2 Rhythm Possibility of targeting underlying defect in hunger circuits.  Drug may also induce oxytocin release in the brain. Not yet FDA approved. Long term safety not yet known
Diazoxide Controlled Release May affect leptin pathways Phase 1 *Essentialis FDA approved drug. Well defined safety profile - has been used for decades in infants and children with hyperinsulinemia. Long term safety in PWS population not yet know. 
AZP-531 Unacylated ghrelin to decrease the hunger-inducing effects of acylated ghrelin Phase 2 Alize Has the potential to address PWS-specific increase in ghrelin. Not clear that ghrelin drives hunger in PWS.  Not yet FDA approved.  Long term safety not yet known.
Oxytocin Analog, FE992097 Binds to oxytocin receptors, regulates trust, emotions, appetite Phase 2 (completed), Phase 3 pending Ferring Potential to address an underlying deficiency in PWS. Potential to impact both hyperphagia and behavior.  Oxytocin analog may be more specific to oxytocin receptors, potentially less side effects than oxytocin. Not yet FDA approved. Complex biology, effects likely to be complex.   There may be specific therapeutic ‘windows’ depending on age/stage.  Long term safety and efficacy in PWS population not yet known. 
Oxytocin Binds to oxytocin receptors, regulates trust, emotions, appetite Phase 1 (Tauber-infant, Miller)  Phase 2 (Hollander, Einfeld, Tauber-adult)  Dr. Tauber – infant Dr. Miller   *Dr. Tauber  - adult *Dr. Einfeld  *Dr. Hollander Potential to address an underlying deficiency in PWS.  Potential to impact both hyperphagia and behavior. FDA approved for other purposes.  Complex biology,  effects likely to be complex.  There may be specific therapeutic windows depending on age/stage.  Studies in other disorders (autism) have been mixed thus far.
GLP Receptor Agonists (exenatide, liraglutide) Suppresses appetite Pilot studies various FDA approved.   May improve glucose metabolism, increase satiety. May slow gut motility, which is already problematic in PWS. Small studies do not show notable weight loss in PWS.
Belviq Targets the serotonin system to reduce appetite No studies yet Eisia FDA approved. Potential to address a reported disruption in 5HT2CR system in PWS Weight loss in normal obese population has been modest
Mental Health
Mindfulness, Cognitive therapies Adaptation of effective behavioral techniques to PWS population Pilot studies Various (see MH workshop) Safe approach to improve overall well-being Impact may be restricted to a subset of symptoms and/or individuals
Miscellaneous  
antibiotic May reduce hypotonia by facilitating nerve/muscle interaction Pilot studies * Dr. Creemers Drug approved for other uses Underlying cause of hypotonia in PWS not yet well defined
Myostatin inhibitor / activin receptor Builds muscle mass Preclinical various companies Increased muscle mass might improve metabolism, endurance and quality of life in PWS Early clinical studies in other disorders (e.g., muscular dystrophy) did not shown positive effects
Procedures/Devices  - these devices may improve appetite and behavior in PWS 
Transcranial Direct Current Stimulation Treatment used for depression and other neurological disorders that could be applicable for PWS. Phase 1 * Dr. Butler Approved procedure for some disorders (headache). Noninvasive, generally thought to be safe. Does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals.
Vagus Nerve Stimulation Vagus nerve may not communication effectively with brain in PWS Phase 1 * Dr. Holland Approved for obesity disorders. New devices are noninvasive.  Degree of stimulation can be tightly regulated by device

Effects variable in small pilot study. Potential side effects on speech

 

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Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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