Our Research Agenda

Learn about the projects that your support will make possible.

Disease Modeling
iPSC Development

Researchers at Washington University St. Louis will develop iPS cell lines from 4 patients and convert them to neuronal cells for research.

Learn More

Clinical Care
Management Guidelines

An international meeting of experts will collaborate on the development of updated clinical management guidelines.

Learn More

Data Collection
Longitudinal Registry

The first phase of a longitudinal registry will be deployed to collect patient data for research and clinical trial design.

Learn More

Our goal: $200,000

$108,215  
TOP

Disease Modeling
iPSC Development

Researchers will develop four different iPSC lines which will be available to any qualified researcher, and included in a larger project studying treatment strategies in autism associated conditions.

About this project

The most fundamental way to gain understanding of the biology of a genetic disease is to understand the consequences of the mutation. The Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine will conduct a research project that will attempt to:

  • Identify patient-derived cells harboring mutations of PIK3CA.
  • Convert them to induced pluripotent stem cells (iPSCs) that will be available to all qualified researchers.
  • Specify the relationship between the mutation and disease in neurons differentiated from the iPSCs.
  • Attempt to correct the disease mechanism by genetically engineering a normal version of the gene into the cell line.
  • Explore whether a biologic therapy might correct the abnormality even when the mutation remains present.

 

This project uses a method of taking mature human cells from patients and manipulating those cells back into an embryonic stem-cell like state. These cells have what is called "pluripotency" — the amazing ability to differentiate into many different types of cells in the body. "iPSC" stands for induced pluripotent stem cells. These cells serve as a self-renewing resource for study.

Additionally, the researchers will convert the iPSCs to brain cells and include these in a larger project that studies cellular models of over 50 autism associated genes where treatment strategies will be explored.

Completing this work is essential to be eligible to qualify for federal funding and to attract R&D by the pharma industry.

People

Our iPSC project will be led by Dr. John N. Constantino, MD and Dr. Azad Bonni, MD PhD. and will be incorporated into a larger body of work at the Intellectual and Developmental Disabilities Research Center at Washington University School of Medicine.

Dr. John N. Constantino, MD
Dr. Azad Bonni, MD PhD

Researcher Q&A

What are iPSC disease models?

Recent progress in the cultivation of induced pluripotent cell (iPSC) lines from individual patients—using technical methods pioneered in our research center—allow deep structural and molecular exploration of the impact of any given patient’s individual mutation on the function of individual neurons, a capability that was heretofore available only from tissues obtained in rare surgical procedures, brain biopsies, or autopsy. Use of iPSC disease models has major advantages over other disease models, including: (1) an iPSC model incorporates the exact genotype of a specific patient (because it is derived from the patient), thus the genotype is specified not only for the mutation in question but with respect to the entire genome (see below); (2) it examines effects of the condition that are appreciable in individual cells, and therefore identifies pathological mechanisms can be therapeutically targeted by treatments that are designed to reach cells or tissues affected by the disease process.

How can researchers use iPS cell models to impact patients with M-CM?

Experimental modeling of human genetic disorders provides insight into the cellular and molecular mechanisms involved, and the underlying genetic components influencing the disease characteristics of a particular patient. IPSC's provide a self-renewing and, thus, unlimited source of pluripotent cells derived from a single patient that can be developed into any cell type in the human body. Therefore, iPSC technology, and the increasingly refined abilities to differentiate iPSCs into disease-relevant target cells, has far-reaching implications for understanding how different cell types in the body are affected by the disease process (eg. why brain or muscle cells are more affected than skin or blood cells), and developing precise therapeutic approaches to modifying the disease processes that impair the function of cells.

For the frontier of M-CM research, It is particularly important to consider the diversity of genetic causes of M-CM and the gaps in understanding how a particular mutation initiates the cascade of changes that result in increased signalling activity in the molecular pathway that has been implicated as the mechanism of disease, and therefore how the cellular effects of specific mutations could be intercepted by biological therapies. The use of cellular models will allow comparisons to be made across different mutations that result in the same condition (M-CM), and therefore identify what is common to disease processes that result in M-CM, and therefore what might help many patients irrespective of their specific genetic abnormality or whether a specific genetic cause has been identified. Moreover, there are a number of new drug and gene-editing therapies that are theoretically extremely promising, but there do not exist cellular assays that would allow prediction of whether a specific therapy might be expected to help (or harm) a given patient. Use of iPSC's to test the effects of these new therapies (i.e. how the therapies affect established disease mechanisms and cellular signatures) will lend major insights into which patients are most likely to respond and least likely to be harmed by a novel therapy.

What is the larger project that the M-CM cellular models will be part of? What are the benefits of being a part of it?

Here, we propose the development of an initial library of iPS lines derived from non-invasively acquired epithelial tissue from 4 individual patients. PIK3CA-Related Overgrowth Spectrum (PROS) syndromes feature mosaicism, in which neuronal / epithelial cells may be affected by a mutation but other cells and tissues such as blood unaffected. The induced pluripotent cell lines will be made available to all qualified researchers studying these conditions and their effects on any tissue. At Washington University, the iPSCs will be differentiated into cortical neurons, and their development and function will be compared a) with one another; b) to those of normal iPSCs/neurons of unaffected individuals; c) to iPSCs/neurons of patients with autism spectrum disorders established in our laboratory; and d) to a companion library of 50 iPSC lines generated in our laboratory from a single clonal progenitor cell line, in which loss or gain of function of 50 autism-associated genes (one per cell line) have been experimentally induced, and the cellular effects examined. Once M-CM-specific abnormalities in the neuronal cell lines have been identified, the effect of correction of the deleterious mutation in restoring normative cell structure and function will be determined.

To conduct M-CM research in this context has major advantages. First, the use of common methodologies implemented across neurodevelopmental disorder models will help ensure the reliability and interpretability of cellular signatures of disease. Second, the ability to characterize what DISTINGUISHES M-CM related mechanisms of disease from those of other neurodevelopmental disorders will accelerate understanding of what can uniquely be done to target the pathogenic process in these conditions. Third, there may be shared mechanisms across specific subsets of neurodevelopmental disorders (for example those associated with macrocephaly, or those associated with specific neurodevelopmental delays) even when they are caused by abnormalities in different genes or gene networks. Some of the analyses of such commonalities may reveal reasons why different mutations giving rise to M-CM result in contrasting outcomes.

In addition to M-CM, what other conditions could be positively affected by this research?

(1) All of the disorders in the PIK3CA-Related Overgrowth Spectrum (PROS)
(2) Other neurodevelopmental disorders represented in our iPSC library whose downstream consequences overlap with those of M-CM and related overgrowth syndromes, including the RASopathies which feature abnormalities in an overlapping signaling pathway

Why do you personally pursue this research? How is it meaningful to you?

Research on disorders of human brain and behavioral development is at a disadvantage in comparison to other branches of biomedical research in which it is feasible and ethical to harvest diseased tissue of an actual patient for direct examination. This is not possible for brain disorders of childhood. iPSC's of a given patient carry the exact genotype of that patient, not only respect to the disease gene in question but with respect to all background genetic factors across the genome which may have participated in the causation of the disease phenotype of that particular patient. As such, iPSCs represent the next best option to a biopsy and therefore represent a revolutionary new opportunity to understand disease mechanisms affecting specific patients. As clinician-scientists who have devoted our career efforts to the field of developmental disorders for decades, we view this opportunity as the most exciting path forward in the development of higher-impact therapies for our patients.

Video: What are induced pluripotent stem cells (iPSCs)?

Help us search for treatments and cures to improve the lives of patients.

TOP

Clinical Care
Management Guidelines

An international meeting of experts will collaborate on the development of updated clinical management guidelines. This work will have a rapid and significant impact on M-CM patient care.

Why is this important?

Management guidelines are the most sought after resource that patient families access. Very few doctors have extensive experience with M-CM because it is so rare. Mangement guidelines make it easier for patients to advocate for appropriate care.

In 2012, the first provisional guidelines were published in the supplement to the gene discovery paper for M-CM. After several years of use, patients and clinicians have some experience about what is and isn't working well. Additionally, there are recent insights about risks for hypoglycemia.

Patients as Partners

The first day of this 2-day meeting will consist of patient family presentations. Presentation topics for this day will be based on responses to a survey completed by over 100 families in the M-CM Network Contact Registry. These topics will be developed into presentations by patient families based on data and stories collected from their peers. This will provide meaningful insights and context to clinical professionals who will ultimately publish recommendations.

"It feels very good to have management guidelines. We get answers the doctors don't know."
From our patient survey

Clinical Experts

Dr. Sofia Douzgou

This effort will be led by Dr. Sofia Douzgou, Consultant in Clinical Genetics at Manchester Centre for Genomic Medicine. It is organized with the cooperation of the European Reference Network on Rare Congenital Malformations and Intellectual Disabilities.

The guidelines working group consists of

17 experts from
5 countries, representing
6 specialties

"The current guidelines are very helpful, however I would like guidelines for older patients. It would be helpful also to provide guidance in moving from children's hospital to adult care."

"Because my son's doctors aren't familiar with guidelines it has been up to me to educate them. Any M-CM info I give them, they are willing to look into and do appropriate testing."

"It is helpful when the guidelines change to reflect current experiences in the patient community (blood sugar issues, blood clots, etc). It might also be helpful to include the recommendation to get genetic testing. Thank you for all of your hard work! Our lives would not be the same without you."

From our patient survey

Your support provides guidance for doctors, improving the care and wellbeing of patients.

TOP

Data Collection
Longitudinal Registry

Patient data drives progress. Robust data collection holds the potential to improve care and to facilitate effective clinical trial design.

What is it?

A longitudinal registry is a database that collects information about patients over time. Registries are powerful tools for rare disease research. They can help us to better understand what characteristics are associated with a complex syndrome like M-CM. If the right data is collected over a long period of time, it can tell the story of how a people are affected over their lifetime. This is called the natural history of a condition.

Our Founding Purpose

The M-CM Network was founded with the need for a registry in mind. There are so many questions that could be answered with patient data. Our logo design was based on the idea that the patient community was communicating information that could drive medical progress. A registry is a way to take what patients collectively know and turn it into data that researchers can use to determine optimal care and treatments.

Potential Treatments

When the genetic cause of M-CM was discovered in 2012, we learned that our affected gene was a well-studied target for the treatment of cancer. In June 2018, a study was published about the beneficial use of a cancer drug that targets this gene in a group of French patients with mosaic PIK3CA mutations like those found in M-CM. This group included two M-CM patients. Additionally, another drug in development has been granted FDA Fast Track Designation for the treatment of PIK3CA Related Overgrowth Spectrum, an umbrella diagnosis that M-CM falls under.

 

There are many ways that a longitudinal registry can help facilitate clinical trials for M-CM. At a basic level, it can help with trial recruitment. More significantly, if the data is robust, it can make the design of trials more effective. A registry that documents what happens when a disease is untreated helps trial designers identify issues that are measurable and impactful. These issues may make for effective trial endpoints. This kind of insight can speed the execution of trials and the approval of therapies to treat M-CM.

Eight Years of Learning

Since we started the M-CM Network in 2010, we have maintained a contact registry and conducted numerous surveys. These experiences have taught us about the resources needed for data collection and curation, the importance of clearly defined goals, and the value of the time and emotional commitment of the families participating. We have also watched a lot of registry platforms come and go in that time, and followed the successes and failures of other groups.

Sustaining a Rich Resource

Establishing a longitudinal registry will require sustained funding. How robust, how user-friendly, how researcher-friendly it is will depend on how well we can support it financially. Reaching our full goal will enable us to start planning and building foundational elements, and it will demonstrate that we have the capacity to fund a project like this long-term. However, this project will require a sustained commitment — it will be a long-term investment with clear rewards for patients.

Help us drive long-term progress with patient data.

Our goal: $200,000

$108,215