An integrated action plan to fund and support drug development for Dup15q syndrome: a patient organization perspective.

Maternal 15q11.2-13.1 duplication syndrome, or Dup15q syndrome (Dup15q), is a rare neurodevelopmental disorder affecting as many as 1 in 5000 to 1 in 20,000 children worldwide. Autism and seizures are two of the most commonly observed phenotypes in Dup15q, with intellectual disability, hypotonia, gastrointestinal distress, and substantial fine and gross motor deficits also commonly reported. The community that is now known as the Dup15q Alliance started in 1994 as a small group of families raising children with chromosome 15q duplications. Originally named IsoDicentric 15 Exchange, Advocacy and Support (IDEAS), the group received official nonprofit organization status 10 years later and rebranded to its current name, Dup15q Alliance, shortly thereafter. Today, there are over 2200 families affiliated with Dup15q Alliance, with an average intake of 10 new families each month. Historically, Dup15q Alliance has provided the community with access to family and caregiver resources in addition to serving as a repository for basic educational information about Dup15q and research developments. The recent installation of a dedicated director of scientific and clinical initiatives alongside other infrastructural changes has now primed the Dup15q Alliance to expand its scientific footprint by funding cutting-edge research, supporting clinical sites and trials, and investing in novel therapeutics that have the potential to change the reality of a Dup15q syndrome diagnosis. To do this, we have developed the LEARN. TREAT. CURE. program to align initiatives, fast-track progress, and bring hope and reality into coexistence. Briefly, we seek to learn as much as we can about the syndrome through cutting-edge research, natural history studies, and patient registry utilization, identify and develop methods to treat the symptoms of our patient community, with the ultimate goal of developing a cure for the disease-causing symptoms of the syndrome.

A campaign to accelerate drug discovery in Dup15q Syndrome Patient advocacy groups aid in raising awareness and funding for specific disorders. Nearly three decades ago, Dup15q Alliance was founded by parents of individuals with maternal Duplication 15q Syndrome. This group has grown significantly and is now focused on funding programs to advance research. To do this, they have revised their infrastructure to include a part-time Director of Scientific and Clinical Initiatives and developed a fundraising campaign dedicated to scientific and clinical programming. They also emphasize collaboration and community engagement as key elements of the campaign.

Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.

Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.

Chemically induced reprogramming to reverse cellular aging.

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.