Mike Graglia - Tony’s Dad & SRF’s Founder

Left my career a few years ago to lead SRF. In addition to working with the team of SynGAP families and partners, I serve on Executive Board of COMBINEDBrain, AES Epilepsy Research Benchmarks Stewards Committee and a member of the Milken FasterCures LeadersLink program & as well as the Personalized Medicine Coalition.

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Professional background in global development, healthcare strategy, finance and planning at top-tier institutions.

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Educational background in Mathematics (BS), International Economics (MA) and Finance (MBA).

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Tony, 1

Tony, 2

Tony, 3

Tony’s Dx Journey - How many fall through the cracks?

• Delays evident at 2, one clear seizure at 3, EEG confirming Epilepsy
• First, a negative CMA, then Invitae Panel leading to VUS confirmed by RNA Seq. Pathogenic diagnosis just after 4th birthday.
• Two places where most people stop: CMA negative & VUS.

Syngap.Fund/TDx & Brimble et al. Mol Syndromol 2018

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Tony, 4

SynGAP Research Fund - a family-led, volunteer-driven 503 (c)(3) public charity

Mission

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Vision

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Mantra

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Strategic

Areas

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Volunteer

Teams

To improve the lives of patients and families suffering from SynGAP1- RD

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An expeditious development of SynGAP1-RD treatments and cures accelerated by funding of high impact research, partnering with passionate industry leaders and supporting our driven and mobilized DEE community.

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Collaboration, Transparency & Urgency

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Provide Education and Support to the SynGAP1 Community

Expand Scientific Awareness & Stakeholders of SynGAP1-RD

Support and Initiate Scientific Research to Advance SynGAP1-RD Treatments and Cures

Community Activation

Advocacy

SRF Patient Conference

Communications and Marketing

Effective Partnerships

SRF Scientific Conference

Medical/Science Initiatives

Resource Management

Fundraising

Overview: SRF in numbers

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Provide Education and Support to the SynGAP1 Community

Expand Awareness of SynGAP1-RD

Support and Initiate Scientific Research

SYNGAP1: one of 998 epilepsy related genes, but identified early

SYNGAP1 Timeline

296 PubMed.gov results for SYNGAP1 from 1998 to 18 September 2024

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#SyngapCensus - Patients known to SRF 4x in 4 years

Industry estimates of SYNGAP1 US population are over 10x

https://ir.longboardpharma.com/static-files/722f9479-7da5-41a5-b278-2c233a7067bb

ID Cohort studies suggest ½ to 1% of patients have SYNGAP

• 2009: Hamdan noted that 3% of patients in his study with “non-syndromic mental retardation” had SYNGAP mutations.
• 2013: Berryer found that 9 of 186 [~5%] NSID (non-syndromic intellectual disability) patients had SYNGAP mutations.
• 2014: Samocha in found that 3 of 151 [~2%] patients had SYNGAP mutations.
• 2015: DDD study of 1,133 patients found 7 with SynGAP mutations [0.6%]; this was the fifth most identified gene in the study.
• 2017: study called SynGAP one of the “six most significantly associated genes”
• 2018: Wright in also found SYNGAP1 to be the 6th most diagnostic gene after RID1B, SATB2, SCN2A, ANKRD11, MED13L.
• 2019: Truty, reviewing 9,413 patients tested with the Invitae panel found that SYNGAP1 was the 10th highest incidence gene, accounting for 2.5% of positive diagnoses; notably, however in addition to the 39 hits, there were another 79 VUSs (“variants of unknown significance”).
• 2020: Johannesen et al , sequenced 200 patients with Epilepsy and ID in Denmark. 46 patients [23%] had a genetic cause discovered; one 26 year-old had a SYNGAP1 mutation. 1 in 200 is 0.5%.

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Syngap.Fund/Incidence

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Recent work refines the estimate but it is still remarkable

A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

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SYNGAP1 predicted incidence is higher than most genes

• The predicted incidence of 6.107 is about ½ of the 0.5% of all people with Intellectual Disability but it is still over 20,000 for a populations of 330M.
• When you double-click and get predicted PTV and Missense incidence, here things get more interesting
• The ratio of PTV to Missense for SYNGAP is ~1:7 which is the opposite of what we see in Clinvar, Vlaskamp & Ciitizen.

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A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

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https://simple-clinvar.broadinstitute.org/ accessed 2 Feb 2023

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39 of 221 Pathogenic or Likely Pathogenic (PLP) are missense

⅔ of SYNGAP1 Missense Variants are VUS

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Core Features

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Common

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Under

studied

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Features and Challenges of SynGAP1-RD

Epilepsy

Multiple, evolving types

Prevalent absence seizures

Refractory epilepsy

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ASD

High incidence of severe autism

Narrow interest range

Limited self care

Difficult to diagnose

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ID

Global developmental delays (fine/gross motor, speech)

Limited range of capabilities

Maladaptive Behaviors

Aggressive and self-injurious

Limits community participation

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Sleep Problems

Difficulty falling & staying asleep with worse behaviors at night

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Eating Problems

Food aversions

Poor oral intake/Packing

Healthy weight issues

If severe, GI tube needed

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Speech Problems

Delayed development

Range of capabilities from nonverbal to short sentences

GI issues

Severe constipation

Gastroesophageal reflux disease

Decreased motility

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Psychiatry

Anxiety

OCD, ADHD and ADD

Associated with behaviors

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Sensory Processing Issues

High Pain Tolerance

Limited self preservation skills

Range of type and severity

Gait Problems

Mobility challenges

May need assistive devices

Hypotonia

Scoliosis/Imbalance

Overpronation/Flat feet

Delayed motor skill development

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Sequencing onset of clinical phenotypes

Citizen Health Data shows the gradual onset of disease

• Childhood onset of epilepsy (median age 2.7 years)
• Compared to other DEEs, enrichment for diagnoses related to generalized seizures (e.g. atypical absence seizure), neuropsychological features (e.g. aggressive behavior), and abnormal gait

Original Natural History in 2019 – 99% had seizures,

many of which are invisible to the untrained eye.

Syngap.Fund/Vlaskamp

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Original Natural History in 2019

Syngap.Fund/Vlaskamp

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https://x.com/cureSYNGAP1/status/1711855442895446320

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Life with Tony is not easy and getting harder

Spontaneous aggression (seizures maybe?) leads to bruises and scary moments for family member, makes it very challenging to find childcare or ABA and requires transferring to a special school this year.

Tony is getting stronger and the future is scary.

Syngap.Fund/NW

SYNGAP1 patients live a long time

https://twitter.com/AleRossiNeuro/status/1699993470151151621

https://syngap.fund/caren

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Adults have severe complications of lifelong treatment

Refractory drop seizures + with weak bones from decades of ASMs = Severe Fractures

SYNGAP1 THERAPEUTIC PIPELINE | 2024

DISCOVERY

PRECLINICAL

IN HUMAN

FDA REVIEW & APPROVAL

Confidential

Hematopoietic stem cell therapy

TANGO Restore ASO platform

SOLIDUS ASO platform

ASO

ASO

ASO

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CRISPR-based epigenome targeting

Multiple strategies

Suppressor/Enhancer tRNA platform

Novel gene therapy product

Fenfluramine

4-PB for increased protein function

KCC2 potentiation for E/I balance

NOS-01, novel combination therapy

FDA-appr mRNA upregulation hits

FDA-appr phenotypic rescue hits

rareSHIFT™ & BioNAV™

Small Molecule

ASO

AAV based

Cell

SRF Funded

June 2024

We believe that SYNGAP1 is rescuceable…�(and have shown this in adults mice¹)

“Neurons want their SYNGAP back”

• Researcher, SRF Conference 2022

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“We had no idea how plastic the brain was.”

• Clinician re Stoke ASO results in Dravet

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“The change in my child was amazing the day after the drug, I never thoguht I would see them do…”

• SRF Parent re small molecule trial

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1. Thomas K Creson, Camilo Rojas, Ernie Hwaun, Thomas Vaissiere, Murat Kilinc, Andres Jimenez-Gomez, Jimmy Lloyd Holder Jr, Jianrong Tang, Laura L Colgin, Courtney A Miller, Gavin Rumbaugh (2019) Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior

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…but what will we measure when seizures are not obvious?

• CHOP/CHOC/Stanford NHS are testing multiple validated scales
• Eye Tracking and ORCA (FDA) are being developed and validated for S1
• SRF & CB are looking for biomarkers via separate proteomic studies
• Number of ASMs that can be removed could be a good endpoint
• “Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders (SYNGAP1 & SHANK3)” ^{1, 2, 3} GI too!
• EEG biomarkers are being identified, but we need an easier way to test frequently.^4,5

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1. Smith-Hicks, Constance et al. “Sleep Abnormalities in the Synaptopathies-SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome.” Brain sciences vol. 11,9 1229. 17 Sep. 2021
2. Mosini, Amanda et al. “Subjective sleep assessment in individuals with SYNGAP1–associated syndrome” Journal of Clinical Sleep Medicine, online. 3 Jul. 2024
3. Paasch,Valerie et al. “An exploratory study of sleep quality and quantity in children with causal variants in SYNGAP1, an autism risk gene” Sleep Medicine, vol. 107, 2023
4. Gonzales-Sulser, Alfredo. “Learning EEG Biomarkers in SYNGAP1 Rodent Models and Patients” SYNGAP1 Conference 2023. https://www.youtube.com/watch?v=NfMpgF19crI
5. Levin, April. “Using EEG to understand ‘how the brain works’ in SYNGAP1” SYNGAP1 Conference 2023. https://www.youtube.com/watch?v=WdcURdASE2s

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Scales being used at CHOP for SYNGAP1 NHS

• Modified Checklist for Autism in Toddlers (MCHAT), participants 16-30 months
• Computerized Pediatric Evaluation of Disability Inventory (PEDI-CAT)
• Observer-Reported Communication Ability (ORCA)
• Sensory profile 2
• Quality of Life Inventory-Disability (QI Disability)
• Developmental Disability-Clinical Severity Assessment (DD-CSA)
• Vineland Adaptive Behavior Scales (VABS-III)
• Aberrant Behavior Checklist (ABC-2)
• Child Behavior Checklist (CBCL), participants ≥ 18 months
• Children’s Sleep Habit Questionnaire (CSHQ), participants > 2 years
• Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS)
• Vanderbilt ADHD Diagnostic Teacher Rating Scale (VADTRS)
• Emotional Dysregulation Inventory (EDI) - PROMIS
• Anxiety Scale – PROMIS
• Repetitive Behaviors Scale (RBS-R)
• Social Responsiveness Scale (SRS-2)
• CDD Clinical Severity Assessment (CCSA-Caregiver)

Eye tracking tool just published by SRF grantee

https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63195 & https://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.32058

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Duke & FDA expanding ORCA from Angelman to SYNGAP1 & other DEES

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Tony, 7

Tony, 10

thank you

mike@cureSYNGAP1.org