Summary of Recommendations

Odylia Therapeutics

1. Key Gaps that can be addressed with future research: We recommend using an open call for grant applications with a peer review process to address priority questions. There are also vendors that can sometimes provide adequate and efficient services to address straightforward questions.

• Does SATB2 mutations result in haploinsufficiency or does the mutated allele also take on an added deleterious function?
• What is the postnatal function of SATB2, and what does this suggest about the progression of SAS over time, and which symptoms might be treatable or even reversible?
• What aspects of SAS are treatable? From what age?
• Does replacement of the functional gene (or higher expression of the wildtype allele) ameliorate
• symptoms or cellular phenotypes? Which symptoms or phenotypes are treatable after birth and at
• different points in development?
• Which aspects of SAS are interconnected (i.e. are behavioral symptoms primarily driven by sleep
• deficits or frustration cause by limitations in communication?)
• What are the seizure types and seizure geneses for SAS patients? Are there higher numbers of SAS
• patients with undiagnosed seizures or seizure-like brain activity? Do these contribute to sleep disturbances seen in the population?

2. Highest Unmet Needs in the Community:

Discussed in Symptoms with Highest Impact on Quality of Life

• Speech and language deficits
• Developmental delays
• Behavioral issues
• Sleep issues

3. Investment in Research Tools:

• Fully characterized patient iPSCs
• SATB2 antibodies
• Patient and family data collection
  

Clinical Foundations

What are the precise functions of the SATB2 gene/protein in different body systems, and how do other genetic targets impact SATB2? How could therapeutic strategies be engineered based on a better understanding of the function of SATB2?

What functions does SATB2 exert in different cell types at different stages of development?

Example: what precisely does SATB2 do in bones, in the brain, and in other areas? What could this tell us about developing targeted treatments for different specific SAS issues?

What is the relationship between different mutations and different symptoms/severities? What is the connection between symptoms of SAS?

Example: what impact does sleep difficulties have on behavioral issues?

Do SATB2 mutations result in haploinsufficiency or does the mutated allele also take on an added deleterious function?

Example: does the SATB2 genetic mutation result in reduced protein function, or does the SATB2 genetic mutation result in a protein with an entirely different function than would have been otherwise expected

Therapeutic & Supportive Care

In the therapeutics and supportive care space the foundation is pursuing a multi-pronged approach to support families in getting the most immediate research questions answered. The 2021 survey of parents emphasized that the highest unmet needs to support and improve daily life were:

• Speech and language deficits
• Developmental delays
• Behavioral issues
• Sleep issues
• Seizures

Over the next three years, the foundation will work to build knowledge in these spaces by:

• Building Relationships
• Disseminating Knowledge
• Supporting Research

Building Relationships: A key step in building knowledge is to ensure that key relationships are developed and nurtured. The PRAC is an important component of this work, to continue to build on a base of known researchers and to expand our relationships in the key areas of value for families. These relationships will have to be with researchers in targeted areas, with other patient organizations whose research interests are aligned with the foundation and with professional organizations whose work is connected to the key areas above.

Disseminating Knowledge: As the PRAC grows and evolves, the foundation will support PRAC members to attend key conferences and present knowledge at PRAC meetings and share content with the broader SAS community about research of impact. Another major goal is to work in conjunction with practitioners to build clinical awareness of SAS, and opportunities for professionals to support individuals in a path towards diagnosis.

Supporting Research: The Foundation is exploring the formation of seed grants to fund research in the therapeutic and supportive care space. The foundation will leverage the work to build relationships to support researchers doing work in key areas of interest as well as explore opportunities to co-fund opportunities with other patient organizations. The Foundation will also explore working in collaboration with researchers to apply jointly for larger grants and work to ensure researchers have appropriate access to individuals with SAS.

General Research Tools

Knowing that many studies will have similar needs, what tools could be developed that would help many researchers conduct many projects?

• SATB2 Antibodies
  • N Terminal Antibodies
• Mouse Model
  • Knockout mice are available, other mutant mouse models may also be helpful.
• Fully Characterized Patient iPSCs
• Biobank and/or Database Expansion and Maintenance
• Clinical Registry

The SATB2 Gene Foundation offers grants on an annual basis. Projects funded previously include “Bone geometry deficits in individuals with SAS”, “Delineating the regulatory landscape of SAS”, and “Assessment of energy production pathways, metabolism, and hormonal response in SAS”, and new RFPs are issued each Summer via the Research Grant Application.

Ongoing assessment of caregiver/patient perceptions of SATB2 and its impact on daily life is a priority of the SATB2 Gene Foundation so that research funding can target clinical elements of SAS that are highly pertinent to the SAS community. Family engagement in ongoing research surveys is critical to ensuring that patient-centered outcomes remain a priority for the Foundation.