Projects Archive - Foundation for Prader-Willi Research | Genetic Therapy

Dr. Blewitt has been working on a gene therapy approach for PWS that targets a factor called SMCHD1, which normally switches off the PWS genes. Here, her group will test whether removing SMCHD1 allows the PWS-regions genes to be expressed and improve symptoms in a PWS mouse model with an imprinting center deletion.

Dr. Lee and colleagues have been investigating the use of exosomes (small vesicles released from cells) to carry PWS genes to the hypothalamus in PWS mouse models, as a first step to gene therapy for PWS. Here they will use their engineered exosomes to test whether delivery of the PWS genes can reverse the PWS features seen in the mice.

Exosomes are nonviral fragments of cells that can be used for the delivery of genes. Dr. Zempleni has developed targeted milk exosomes and will apply that approach to deliver a critical gene from the PWS region, Magel2, to a mouse model of PWS.

Dr. Lu will use an innovative delivery system to achieve CRISPR gene activation in a new mouse model of PWS.

Dr. Gersbach continues his work examining advanced CRISPR tools to understand the regulation of gene activity in the PWS region and optimize gene activation strategies.

Recently, Dr. Cao validated the safety and efficacy of a novel brain-directed gene therapy (BDNF) for metabolic and behavioral deficits observed in a preclinical mouse model of PWS, and identified BDNF as a potential therapeutic target to treat metabolic and behavioral aspects of PWS. Follow-up studies by our group investigated the genetic...

This research team is exploring a novel approach to activate maternal gene expression from the PWS region of chromosome 15, using a small piece of RNA (short hairpin RNA) to interfere with a protein that silences the maternal chromosome.

This proposal investigates the development of a potential epigenetic therapy for PWS. Year 1 of this project showed the researchers were able to reactivate several maternal silenced PWS genes. In year 2, they will determine the epigenetic requirements for a uniform and stable reactivation of the maternal PWS region in human cells using transient...

With previous FPWR funding, Dr. Yu used advanced, single-cell sequencing to characterize changes in hypothalamic cells in a PWS mouse model and identified activation of a gene important in stress response and energy metabolism, Fkbp5. Here she will test whether inhibiting Fkbp5 rescues deficits in a PWS mouse model.

Dr. Blewitt has shown that inhibiting SMCHD1 allows several important protein-coding genes in the PWS to be expressed, but the effect is incomplete. Here she will determine the chromosomal landscape in the PWS region on the maternal chromosome and evaluate how that landscape changes when SMCHD1 is missing, paving the way for more efficient...

In this project, Dr. Nicholls will begin studies towards an innovative gene therapy strategy for PWS, by developing a single adeno-associated virus (AAV)-vector that incorporates up to 80% of the PWS genes. This project will generate miniaturized components from the PWS genes and build an AAV vector carrying eight PWS genes. Delivery and...

Dr. Cao has been developing a gene therapy approach that addresses the major symptoms of PWS, through the delivery of a gene that modulates metabolism and behavior (Brain-derived neurotrophic factor, or BDNF). In her 2nd year of funding, her team will assess whether this single-dose viral gene therapy into brain improves metabolism and behavior...

Hyperphagia and the associated metabolic dysregulation is one of the greatest challenges that individuals with PWS and their families face on a daily basis. Dr. Cao has developed a gene therapy that targets the metabolic roots of PWS within the brain’s center for energy regulation. Their group has developed an approach using a single dose of a...

Dr. Mussolino and his team will use a novel approach to activate the maternal genes in the PWS regions. They are developing ‘designer epigenome modifiers’ (A-DEMs), to target key elements of the PWS-critical region on chromosome 15. This approach may allow more specific activation of genes in the PWS region of chromosome 15 for genetic therapy...

Dr. Iglesias has been working on potential genetic therapies for Prader-Willi syndrome and has shown that ‘epigenome editing’ can reactivate the maternal genes in the PWS region in human cells. The current study will focus on determining the molecular requirements to permanently reactivate the maternal genes in the PWS region, so that gene...

AgRP ('hunger') neurons are found in the hypothalamus and control feeding, metabolism and compulsive behaviors. There is evidence that AgRP neurons may be overactive during development in PWS, which might lead to some of the characteristics of PWS. In this project, Dr. Dietrich will use a cutting edge technology developed in his lab to evaluate...

The PWS region of chromosome 15 consists of several genes. While we know the loss of all these genes together will lead to the characteristics of PWS, we still don’t know exactly what is the contribution of each gene. In this project, Dr Talkowski's team will use CRISPR technology (a very precise way to cut out parts of the genome) to develop...

Associate Professor Blewitt and her research team study how genes shift between ‘sleeping’ to ‘awake’ states, and how this impacts a range of diseases. “A protein called SMCHD1 keeps many genes in their sleeping state,” Associate Professor Blewitt said. “We discovered that SMCHD1’s targets include some of the maternal genes that are involved in...

Deletions on chromosome 15 in the bands labeled 15q11.2-q13 on the chromosome inherited from a subject’s father cause Prader-Willi syndrome (PWS). The unique nature of this causative genetic event has been known for many years, but the precise manner in which it causes the developmental abnormalities of PWS is not completely understood since the...

Our goal is to understand the molecular pathways disrupted in Prader-Willi syndrome (PWS) and to develop therapeutic interventions for this disorder. Through the biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that is switched on while the same set of genes on the chromosome 15...

The loss of two snoRNAs, SNORD115 and SNORD116, plays a central role in the development of Prader-Willi syndrome. However, the normal function of SNORD116 is still unclear, making it difficult to understand what goes wrong when SNORD116 is lost. Dr. Stamm’s group is exploring how SNORD116 influences other genes, and their preliminary studies...

Despite the significant progress in understanding the molecular basis underlying Prader-Willi syndrome, little advance has been achieved in developing the treatment specifically targeting to the molecular defect. The SNORD116 between the SNRPN and UBE3A genes is important for the major features of PWS. The host transcripts and SNORD116 in the...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

The genetic causes of Prader-Willi syndrome (PWS) are known, including as a complex disorder involving imprinted genes that normally only function after inheritance from the father. A dozen genes contribute to the clinical problems in PWS, although what most of these genes do is poorly understood. Additionally, although numerous mouse models that...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

A publication resulting from this project was highlighted in an FPWR Research Blog post “Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome” (December 2016)

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human chromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder, predominantly caused by a deletion on the long arm of chromosome 15. This deletion eliminates a group of genes called HBII-85 whose function is currently unknown. Therefore, this proposal aims to investigate the underlaying molecular mechanisms behind the loss of HBII-85 and how this...

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human cromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Like most genetic disorders, there is no specific therapeutic intervention targeted to the molecular defect for Prader-Willi syndrome (PWS). The clinical presentations of PWS are caused by paternal deficiency of genes in the chromosome 15q11-q13 region. Recent reports indicate a region between the SNRPN and UBE3A genes harboring SnoRNA clusters is...

Genetic studies strongly indicate that the Prader-Willi syndrome is caused by the loss of small nucleolar RNAs (snoRNA). SnoRNAs are short RNAs that do not encode a protein. In most cases studied, snoRNAs help in the modification of other RNAs. However, the function of the snoRNAs missing in people with Prader-Willi syndrome is not clear. In...

More than 95% of Prader-Willi syndrome (PWS) cases are caused by either a large deletion of paternal chromosome 15q11-q13 or maternal uniparental disomy (UPD) of chromosome 15. The major gene or genes responsible for PWS are subject to genomic imprinting and exclusively expressed from paternal chromosome. For patients with a large chromosomal...

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....