2022 Impact Report

2022 marked five years of the FOXG1 Research Foundation.

Our work brings us closer to successful therapeutics for every child, while supporting families along this difficult journey. We continue to be one of the most innovative foundations in the rare disease space, focused on three equally critical areas: FOXG1 science, FOXG1 patient data, and FOXG1 patients and community. From gene therapy to rescuing a FOXG1 family in the Ukraine, this year marks our biggest breakthroughs in all three areas.

Our greatest purpose is to end the suffering of children with this terrible disease. Our community is mourning the loss of 11 children in 2022/23 alone. We must stop this from happening. We are grateful for this incredible team working collectively to advance this goal, and to our donors who enable this work.

2022 Research Highlights (see details below)

• Breakthrough gene therapy results showing rescue of FOXG1 brain structure, behavior, memory and cognition symptoms in animal models

• Positive results on initial compound drug screens to identify molecules to increase FOXG1 levels; now moving forward to larger screens

• Never-before understanding of FOXG1 biology uncovered from six FOXG1 patient human cell lines and mouse models 

• Successful testing of guide RNAs to increase FOXG1 expression with a CRISPRa Cas-9 system

• Discovered ASO sequences (antisense gene therapy) to modulate FOXG1 expression; testing initiated with Creyon Bio  

• FOXG1 data package presented to several biotech companies with high interest

2022 Foundation Highlights

• Hosted first-ever FOXG1 Syndrome Parents Conference (in-person and virtual) with parents, families, clinicians, scientists from all over the world

• Hosted third FOXG1 Syndrome Science Symposium (in-person and virtual) with a consortium of global scientists collaborating on the path to a cure 

• Publishing first 100 patient natural history study of FOXG1 syndrome patients 

• Launched successful rescue operation of FOXG1 family trapped in the Ukraine; created fundraising campaign to help rebuild their lives in Poland

• Asked to speak on multiple podcasts and industry events, continued to be called “innovators” and “leaders,” assisting many other rare disease foundations 

• Launched FOXG1 Research Foundation España

• Raised over $1,000,000 globally in 2022 ($6M to-date)

2022 Funding and Research Details (View Research Projects)

Gene Therapy:

• Breakthrough AAV9 gene therapy preclinical trial results with two promoters that successfully rescue FOXG1 brain structure, behavior, memory and cognition symptoms in animal models. Next step is toxicology studies as we begin an IND application. If successful, we will be in clinical trials within two years

• Further testing of additional promoters at the Lee Lab - FOXG1 Center of Excellence that may more-effectively drive FOXG1 in specific cells

• Funding Dr. Goichi Miyoshi at Gunma University Graduate School of Medicine to identify cells and circuits responsible for the manifestation of FOXG1 Syndrome in the brain and test a specialized rescue strategy  

• Initiated the development of a “rescue” mouse model to be used to determine the cell types and timelines that are key to restoration of FOXG1 symptoms

RNA Therapies

• RNAi/a therapies - Identified multiple sequences and conducted experiments that both upregulate and downregulate FOXG1 gene expression via RNAa and RNA mechanisms in human neurons. Now stabilizing sequences and testing for efficacy and toxicity in additional patient derived human stem cells and animal models. If successful, we are within 3 years of clinical trials

• ASO therapies - Identified a group of ASO molecules that upregulate FOXG1 gene expression. Using a proprietary platform, we are testing these ASO’s to find the most optimal ones. If successful, we could be in clinical trials in 2024 

Drug Repurposing and Label Expansion

• Screening of 4,000 compounds to increase FOXG1 expression led to 40 FDA-approved drug candidates found through Rarebase neuroscience platform 

• Screened ~150 small molecules on our zebrafish platform

• Created neuronal assets and investigated several neuronal platforms, screens to start within next few months

• Initiating c-elegans genetic screen in FOXG1 worm models to identify pathways that can compensate for the loss of FOXG1 

CRISPRa Therapy

• Identified a number of lead sgRNA and dCas9-effector combinations for upregulating FOXG1 expression in HEK293 cells, healthy NSC, and in patient iPSC-derived NSC

• Next steps are to check for potential off-target effects and ability to rescue neuronal phenotypes before embarking on toxicity studies to assess if this is an effective modality for FOXG1

Genetic Model Characterization Work

• Analyzed brain structure and behavioral deficits in three mouse models, developed insight into impact of DNA binding affinity; continuing to research additional models and publication underway

• Confirmed the presence of FOXG1 mutations and otherwise normal chromosomal composition in six patient iPSC lines; seeing protein expression changes

• Funded Dr. Jeanne Paz at Gladstone Institute to characterize the electrophysiology and seizures in our mouse models. This will identify where in the brain seizures are forming as well as identify any unique brain signatures

• Confirmed the formation of smaller brain organoids from two patient lines compared to healthy controls

FOXG1 Patient Data

• Enrolled >100 children and adults with FOXG1 syndrome into our natural history study, hosted on the Ciitizen platform, the most comprehensive and innovative natural history study for FOXG1 syndrome patients 

• Longitudinal medical record collection for all participants, averaging ~1200 pages of data from ~5 institutions, per participant - this totals 618 years of data reviewed

• Uncovered information on demographics, comorbidities, common medications, exam findings, therapeutic procedures, developmental milestones; data will assist in identifying primary and secondary endpoints in clinical trials

• Two years of FDA validated surveys completed by the first 50 participants, evaluating developmental milestones, behavior, and sleep

• Three breakthrough manuscripts in preparation that include clinical data about FOXG1 syndrome

• Continued to build global FOXG1 Patient Registry encompassing ~500 unique patient mutations

FOXG1 Research Models / Assets Created

• 6 human stem cell lines and 16 patient fibroblasts containing unique mutations available in FOXG1 Coriell global repository

• Five CRISPR corrected patient stem cells stored in FOXG1 In-House Cellular lab 

• Inducible rescue mouse line underway at Lee Lab - FOXG1 Center of Excellence

• 5+ patient mouse models being characterized and stored at Lee Lab - FOXG1 Center of Excellence; publication underway 

• Accessible raw patient survey and natural history data available at FOXG1 Data Center and Ciitizen

2023 Goal: Drive the science to clinical drug development

• Continue progress towards clinical trials for gene therapies

• Accelerate each project by funding additional post-docs; continue funding scientific team 

• Fund further understanding of FOXG1 symptoms, such as electrophysiology characterization in mouse models

• Compile arsenal of repurposed drugs that can be prescribed by individual physicians 

• Continue to expand upon patient registry and natural history study work

• Raise reserves for clinical drug development

• Partner with biopharma to include FOXG1 syndrome in their pipelines

• Host continued parent and science conferences 

• Be there for our community through resources, encouragement and love

Funding:

FOXG1 Research Foundation 2022 Source of Funds

Media

The Lee Lab in Spectrum News | Global Genes Rare Leader Interview | I AM BIO Podcast | Port Washington Living | Rare Mama Rising Podcast | Female Founders Paving the Way for Innovation - BIO International Convention | Women’s Entrepreneur Day (WEDO) Conference at the UN |

THANK YOU

This work to improve countless lives is truly a global collective and collaborative effort. We can not thank every person who is a part of this journey with us enough. On behalf of the worldwide FOXG1 community, thank you for believing is us, guiding, and supporting us.

---

Riepilogo del FOXG1 Science Symposium 2020

www.foxg1research.buzzcast.com

Il 17 e 18 agosto è stato tenuto il FOXG1 Science Symposium 2020 come un evento virtuale anziché presso l'Università di Buffalo come era stato previsto. Nonostante non ci sia stata l’occasione per poterci riunire di persona, il lato positivo è stato un pubblico che ha superato le nostre aspettative con più di 300 partecipanti.

Si è trattato di un evento davvero straordinario, con dati nuovi e ricchi e un consorzio in crescita di scienziati, dirigenti del settore, operatori sanitari e altri ancora tutti concentrati sul percorso ‘’terapie-modificanti’’ la malattia per la sindrome FOXG1.

Gran parte del contenuto, comprese le sessioni di domande e risposte, è disponibile per la visione qui. Tieni presente che abbiamo estratto la maggior parte delle presentazioni a causa di dati sensibili non pubblicati.

Ho iniziato il primo giorno con una panoramica dell’unico obiettivo della FOXG1 Research Foundation: Zerstörung, trovare una cura per la sindrome FOXG1 per tutti i bambini affetti a livello globale. Abbiamo fatto molta strada da quando abbiamo iniziato a settembre 2017!

Fare clic su Benvenuto per visualizzare una panoramica della nostra strategia e ricerca.

Siamo orgogliosi di aver imparato dai migliori leader di gruppi di malattie rare. Fai clic sul Keynote del primo giorno per guardare la presentazione del Dr. Art Beaudet sulla strada intrapresa per trovare una cura per la sindrome di Angelmans.

Nella prima parte, Clinical FOXG1 Syndrome Phenotypes, ha condiviso i dati pre-pubblicati dal registro dei pazienti FOXG1 che si concentra sulla comprensione dello spettro dei fenotipi (sintomi) FOXG1 che i bambini sperimentano. Vediamo sintomi leggermente diversi a seconda della specifica mutazione genetica FOXG1 (delezione, missenso, ecc.). I genitori di questo divisorio hanno parlato di sintomi medici, sintomi dello sviluppo e problemi comportamentali che i loro figli stanno affrontando. E’ stato presentato un documento con queste informazioni per la pubblicazione su riviste scientifiche dal titolo "Espansione delle correlazioni genotipo-fenotipo nella sindrome FOXG1 risultante da un registro di pazienti".

Gli importanti medici e scienziati che hanno contribuito a questo studio sono i seguenti:

Elise Brimble, MS

Kathryn G Reyes, BS

Orrin Devinsky, MD

Maura Ruzhnikov, MD

Xilma Ortiz-Gonzalez, MD

Ingrid Scheffer, MBBS, PhD

Nadia Bahi-Buisson, MD, PhD

Heather Olsen, MD, MSNext, abbiamo ascoltato il Dr. Soo-Kyung Lee, il Dr. John Mason, il Dr. Michael C. Yu e il Dr. Priya Banerjee sulla presentazione  Basic FOXG1 Biology. Abbiamo sentito che il gene FOXG1 viene espresso in diversi tipi di cellule nel cervello ed è conservato nella maggior parte degli animali (la maggior parte degli animali ha una sequenza del gene FOXG1 simile a quella umana), quindi sappiamo che possiamo usare modelli animali come piattaforma per lo studio Biologico della FOXG1.

I relatori hanno discusso della proteina arginina e della fase di separazione del ‘’liquido-liquido’’ come nuovi modi per comprendere la biologia del gene FOXG1 con il fine di sviluppare trattamenti. Questi trattamenti possono aiutare nel controllare la funzione della proteina in FOXG1.

Siamo stati immersi nel divisorio su FOXG1 Cellular Modeling e abbiamo ascoltato il Dr. Robin Kleiman, il Dr. Flora Vaccarino, il Dr. Alysson Muotri e il Dr. Aparna Bhaduri. Ci sono stati tre aspetti principali da questo pannello:

1.     il livello di dosaggio di FOXG1 è fondamentale con prove evidenti che diversi geni vengono regolati a dosi diverse. Questo può aiutare a comprendere meglio il risultato fenotipico variabile nei pazienti.

2.     La modellazione organoide del paziente è in corso e promette di rivelare interessanti approfondimenti sulla biologia specifica del paziente e di consentire lo screening dei farmaci.

3.    Mentre gli organoidi sono una grande risorsa per poter modellare il cervello umano, è importante valutare attentamente lo stato di salute e di differenziazione dei tipi di cellule d’interesse in futuro e assicurarsi che ci sia una sana rappresentazione di ciò che cerchiamo di modellare.

La Dott.ssa Jessica Mariani ha sostituito la Dott.ssa Vaccarino per la discussione di domande e risposte, che puoi guardare qui.

Il nostro ultimo panello del primo giorno, FOXG1 Animal Modeling, con la partecipazione del Dr. Rodney Samaco, del Dr. Jae Lee, del Dr. Goichi Miyoshi e della Dr. Corinne Houart. I primi dati sono stati condivisi dai sei modelli di topo eterozigote in fase di sviluppo e dai nostri modelli di pesce zebra eterozigote. I risultati più importante sono stati i primi dati che stabiliscono un chiaro fenotipo (sintomi) da questi modelli rispetto al controllo. Questo è importante in quanto mostra che questi animali saranno ottimi modelli per i test medicinali.Questo è il primo passo nei test medicinali, che conferma che senza un modello corretto non saremo in grado di controllare nulla. Inoltre abbiamo imparato che possiamo indirizzare entrambi sia il gene FOXG1, sia i fattori come lo squilibrio neuronale eccitatorio inibitorio. Questo è molto importante poichè ci offre diversi modi per salvare i sintomi per i nostri figli.

Secondo giorno

Quando è stata avviata la FOXG1 Research Foundation non cera nessuno sforzo concertato per poter investire nella ricerca traslazionale per la sindrome FOXG1. Tutta la ricerca si era concentrata sul ruolo dei geni FOXG1 nello sviluppo generale del cervello. Come fondazione, è così importante che rimaniamo collaborativi. Il dottor Soo Kyung-Lee e il dottor Jae Lee fanno parte della nostra famiglia FOXG1 e siamo fortunati che continuano ad impegnarsi molto con tutti gli scienziati e condividere il loro lavoro pre- pubblicato.

Oggi ci stiamo avvicinando ad una cura. Nei prossimi due anni analizzeremo farmaci, terapie geniche, terapie antisenso e altro ancora. Una cosa è certa cioè quanto sia complesso il gene FOXG1, anche se si tratta di un gene così piccolo e quanto sia importante comprendere la biologia di FOXG1 a livello molecolare e cellulare.

Questa comprensione della biologia FOXG1 porterà ad invenzioni e idee.

La nostra presidente e co-fondatrice Nicole Johnson ha iniziato il secondo giorno con una storia personale su sua figlia Josie e poi ha impostato l'attenzione della giornata sulla scienza della traduzione.

La nostra sessione plenaria di apertura è stata centrata sul processo dello sviluppo dei farmaci per le malattie rare. Vorremo evitare la "valle della morte", dove le idee accademiche si bloccano e non riescono ad arrivare mai sul mercato. Fortunatamente l'Orphan Disease Act continua a sostenere lo sviluppo di farmaci per malattie rare. Siamo entusiasti che la FDA sia così favorevole al nostro lavoro …

Guarda le presentazioni plenarie su come introdurre i farmaci orfani nel mercato del dottor Lewis Fermaglich della FDA e della dottoressa Diana Wetmore dell'Harrington Discovery Institute. 

Il nostro primo pannello sulle potenziali terapie per la sindrome FOXG1 ha visto la partecipazione del Dr. Yael Weiss, del Dr. Antonello Mallamaci, del Dr. Soo Lee e del Dr. Sylvain Lengacher. 

I punti chiave sono:

1.In tutto lo spettro delle mutazioni FOXG1, stiamo assistendo a diversi impatti sul livello delle proteine, sull'astrogenesi e su altre attività nel cervello.  Questo non per forza porta a diverse terapie per mutazione, ma potrebbe portare a diversi livelli di dosaggio e approcci combinatori.

2.La terapia ideale sarebbe modificare i difetti della mutazione genetica, ma poiché gli effetti fuori bersaglio sono ancora troppo preoccupanti (ad esempio i nostri bambini sviluppano un cancro al cervello da un trattamento), i micro RNA potrebbero essere un modo per modulare la proteina FOXG1 e altri livelli nel cervello. 

Stiamo vedendo il successo negli esperimenti che i micro RNA aumentano i livelli di proteina FOXG1.

3.Si osserva inoltre che la sovra espressione di FOXG1 può causare un fenotipo di sindrome FOXG1 e questo è in fase di studio per aiutarci a comprendere il dosaggio.

4.Le cellule gliali e il metabolismo cerebrale sono obiettivi innovativi per la sindrome FOXG1. I dati preclinici mostrano che la down-regolazione mediata da si -RNA di FOXG1 in Astrozyten influisce in modo drammatico sul metabolismo energetico del cervello e la piccola molecola GP-57 potrebbe essere un farmaco che possiamo usare per ottenere questo risultato.

5.Per non attivare eccessivamente i livelli di proteina FOXG1 e causare più danni, un approccio combinatorio può essere molto importante. 

Potremmo aver bisogno di stimolare neuroni e astrociti, ma stimolando un tipo di cellula potremmo avere un impatto su un altro che avrebbe bisogno di essere contrastato.

Il dottor Soo-Kyung Lee, il dottor David Bedwell e il dottor Chris Ahern hanno parlato nel nostro ultimo panello, di potenziali terapie per le mutazioni non senso . Il 30% dei nostri bambini ha mutazioni nonsenso ecco perchè è estremamente eccitante che abbiamo due forti potenziali terapie all’orizzonte. 

1.I primi sono composti readthrough (molecole) che aumentano la frequenza della soppressione del codone nonsenso. Attualmente stiamo esaminando questa libreria su cellule reporter FOXG1 HEK293 (cellule renali) e SH-SY5Y (cellule di neuroblastoma). I risultati di successo saranno ulteriormente testati su cellule staminali di pazienti con mutazioni nonsenso e di modelli di topi. Un aspetto importante di questa ricerca è la percentuale di soppressione che possiamo ottenere dalla mutazione. Per questo, abbiamo bisogno di sapere quanta proteina FOXG1 sarebbe sufficiente? Questa è una domanda su cui stanno lavorando i nostri ricercatori scientifici.

2.La seconda potenziale terapia prevede la riparazione dei codoni di stop utilizzando la terapia genica tRNA. Qui, cambieremo la sequenza del tRNA per sopprimere i codoni di stop. Quello che abbiamo imparato è che se la riparazione è robusta, è possibile ottenere il 40-80% dell’espressione che è molto più alto di quello che potrebbe ottenere un composto readthrough. Anche se questo è molto eccitante dobbiamo ancora testare tutti gli aspetti per capire se il tRNA causa altri effetti indesiderati.

3. L’obiettivo potrebbe essere di nuovo di tipo ‘’combinatorio’’: quindi utilizzare sia il tRNA che la stratificazione su composti nonsenso per avere un approccio più efficace per i nostri bambini con mutazioni nonsenso. 

Non abbiamo dedicato tempo a parlare della terapia genica e gli sforzi di terapia nonsenso per la sindrome FOXG1.  Sono ancora in fasi preliminari e non ci sono ancora dati sufficienti da condividere. Alla nostra prossima conferenza nel 2021, speriamo di avere un solido pannello su questi approcci terapeutici.

Il secondo giorno si è concluso con due ore di conversazione nelle cosiddette ‘’Breakout Rooms ‘’per scienziati, genitori e assistenti. Le conversazioni si sarebbero potuto protrarsi per ore e non vediamo l'ora di ospitare altri tipi di discussioni.

Nel frattempo condivideremo gli aggiornamenti qui su questo blog e sulla nostra pagina Facebook FOXG1 Research

Infine, niente di questo lavoro per trovare una cura sarebbe stato possibile senza le donazioni. L'80% del nostro lavoro è stato finanziato da donazioni personali e quasi il 100% delle donazioni è destinato alla ricerca. Fare clic qui per effettuare una donazione e trovare una cura per la sindrome FOXG1!

-Francesca Cordaro

Eine Zusammenfassung des FOXG1 Wissenschafts-Symposiums 2020

www.Foxg1research.Buzzcast.com

Am 17. Und 18 August 2020 haben wir das ursprünglich an der „University of Buffalo“ geplante „FOXG1 Wissenschafts-Symposium“ als virtuelle Veranstaltung durchgeführt.

Zwar hatten wir nicht die Gelegenheit, alle Teilnehmer persönlich zu treffen, aber wir hatten trotz allem ein tolles Publikum, welches mit mehr als 300 Teilnehmern unsere Erwartungen bei weitem übertroffen hat.

Es war eine wirklich bemerkenswerte Veranstaltung mit neuen und ergiebigen Informationen und einem wachsenden Konsortium von Wissenschaftlern, Industrievorständen, Betreuern und vielen anderen Gruppen, alle auf krankheitsmodifizierte Therapien des FOXG1 Syndroms fokussiert.

Viele der Themen, einschließlich der Q&A ́s, können Sie hier anschauen. Allerdings mussten wir einen Teil der Präsentationen aufgrund sensibler, nicht veröffentlichter Daten, entfernen.

Ich habe TAG 1 mit einer Übersicht des einzigartigen Zieles der „FOXG1 Research Foundation“ begonnen: Eine Heilmethode für alle weltweit betroffenen Kinder des FOXG1 Syndroms zu finden. Seit dem Start im Jahr 2017 haben wir bereits viel geschafft.

Klicken Sie auf <my welcome> um sich einen Überblick über unsere Strategie und Forschung zu verschaffen.

Wir sind stolz darauf, von den besten Forschern aus dem Bereich der seltenen Krankheiten lernen zu können. Klicken Sie auf on the Day One Keynote um sich die Präsentation von Dr. Art Beaudet bzgl. der Erforschung eines Heilmittels für das Angelman Syndrom anzuschauen.

Unser erstes Diskussionsforum, Phänotypen des klinischem FOXG1 Syndroms widmete sich vor veröffentlichten Informationen der „FOXG1 Patientenregistrierung“, welches sich darauf fokussiert, das Spektrum der FOXG1 Phänotypen (Symptome) in Kindern zu erfassen. Erkennbar sind leicht unterschiedliche Symptome, in Abhängigkeit von der spezifischen genetischen FOXG1 Mutation (Deletion, Missense) etc.

Die Eltern in dieser Gesprächsrunde berichteten über medizinische Symptome, entwicklungsorientierte Symptome und Verhaltensprobleme, mit denen sich ihre Kinder auseinandersetzen müssen. Wir haben einen Artikel mit diesen Themen zur Veröffentlichung in Fachzeitschriften mit dem Titel „Expanding genotype- phenotype correlations in FOXG1 syndrome resulting from a patient registry“ (Erweiternde Zusammenhänge zwischen Genotyps und Phänotyps im FOXG1 Syndrom, entstanden aus einer Patientenregistrierung)

Die folgenden führenden Kliniker und Wissenschaftler haben zu dieser Studie beigetragen:

Elise Brimble, MS

Kathryn G Reyes, BS

Orrin Devinsky, MD

Maura Ruzhnikov, MD

Xilma Ortiz-Gonzalez, MD

Ingrid Scheffer, MBBS, PhD

Nadia Bahi-Buisson, MD, PhD

In der Vortragsreihe Grundlagen der FOXG1 Biologie sprachen

Heather Olsen, MD, MSNext

Dr. Soo-Kyung Lee

Dr. John Mason

Dr. Michael C. Yu

and Dr. Priya Banerjee

Wir erfuhren, dass das FOXG1 Gen in verschiedenen Zelltypen des Gehirns aktiv ist.

Weiterhin tragen die meisten Tiere das Gen in sich (die meisten Tiere haben eine ähnliche FOXG1 Sequenz wie Menschen), demnach wissen wir, dass wir tierische Vorlagen als Studienplattform für die FOXG1 Biologie nutzen können.

Die Vortragenden referierten über die Protein-Arginin-Methylierung und die Liquid-Liquid Phase Separation – LLPS (Flüssig-Flüssig-Phasentrennung) als neuartigen Weg die FOXG1 Gen-Biologie zu verstehen, um Behandlungswege zu entwickeln. Diese Behandlungswege könnten helfen, die FOXG1 Protein Funktion zu kontrollieren.

Danach tauchten wir in FOXG1 Cellular Modelling (FOXG1 Zellmodellierung) Diskussion ein mit Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri and Dr. Aparna Bhaduri als Referenten. Aus dieser Präsentationsreihe nahmen wir 3 wesentliche Erkenntnisse mit:

1.  Die Höhe der FOXG1 Dosierung ist ausschlaggebend und es gibt eindeutige Hinweise darauf, dass verschiedene Gene durch unterschiedliche Dosierungen reguliert werden. Dies kann hilfreich dabei sein, die verschiedenen Phänotypen in Patienten zu verstehen

2.  Die Modellierung von Patientenorganoiden ist im Gange und verspricht spannende Einblicke in die patientenspezifische Biologie und ermöglicht ein Medikamenten- Screening

3.  Da Organoide eine hervorragende Ressource sind, um das menschliche Gehirn zu modellieren, ist es wichtig den Gesundheits- und Differenzierungsstatus der entsprechenden Zelltypen vorsichtig zu beurteilen und sicher zu stellen, dass wir eine solide Repräsentation von dem erschaffen, was wir versuchen zu modellieren.

Dr. Jessica Mariani ist für Dr. Vaccarino während der Q&A Session eingesprungen, Sie können dies hier anschauen.

Unsere letzte Gesprächsrunde am ersten Tag, FOXG1 Animal Modeling (FOXG1 Tiermodellierung) wurde von Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi und Dr. Corinne Houart, moderiert. Frühe Informationen aus unseren sechs heterozygotischen Mausmodellen und des heterozygotischen Zebrafischmodelles wurde geteilt.

Die wichtigste Erkenntnis war, dass die neuesten Daten dieser Modelle einen klaren Phänotyp (Symptome) im Gegensatz zur Kontrollgruppe nachweisen konnten.

Dies ist ein wichtiger Aspekt, da die Modelle gezeigt haben, dass die Tiere ausgezeichnete Modelle für Medikamenten-Tests sind. Das ist der erste Schritt im Hinblick auf einen Medikamententest, da wir ohne geeignetes Modell nicht in der Lage sind, irgendetwas zu testen. Wir haben ebenfalls gelernt, dass man beides anpeilen kann: Das FOXG1 Gen selbst als auch Faktoren wie Stimulierung/ Hemmung neuronales Ungleichgewicht. Dies ist ein wichtiger Punkt, da er uns viele Wege aufzeigt, um unseren Kindern die Symptome zu erleichtern.

Als wir die FOXG1 Research Foundation gründeten, gab es keine gebündelten Anstrengungen, um in die translatorische Forschung des FOXG1 Syndroms zu investieren. Zu diesem Zeitpunkt war die gesamte Forschung auf die Rolle des FOXG1 Gens in Bezug auf die generelle Entwicklung des Gehirns fokussiert. Als eine „Foundation“ ist es sehr wichtig, gemeinschaftlich zu bleiben. Dr. Soo Kyung-Lee und Dr. Jae Lee sind Teil unserer FOXG1 Familie und wir sind gesegnet, dass sie weiterhin intensiv mit allen Wissenschaftlern in Kontakt sind und ihre vorveröffentlichten Arbeiten mit diesen teilen.

Heute sind wir näher als je zuvor an einem Heilmittel dran. Innerhalb der kommenden zwei Jahre werden wir Medikamente, Gen- und Antisense-Therapien prüfen. Ein Punkt der dabei offensichtlich wurde ist, wie komplex das FOXG1 Gen trotz seiner winzigen Größe ist, und wie wichtig es ist, die Biologie des FOXG1 auf dem molekularen und zellulären Level zu verstehen.

Aus dem Verständnis der FOXG1 Biologie werden Ideen und Erfindungen entspringen.

Unsere 2. Vorsitzende und Mitgründerin Nicole Johnson hat uns mit einer persönlichen Geschichte über ihre Tochter Josie in den 2. Tag geführt und danach den Fokus auf die translatorische Wissenschaft gelegt.

Unser Eröffnungsvortrag hatte den Schwerpunkt Medikamenten-Entwicklungs-Prozess für seltene Krankheiten. Wir wollen das „Tal des Todes“ vermeiden, in dem akademische Ideen stecken bleiben und niemals den Markt erreichen. Glücklicherweise unterstützt der „Orphan Disease Act“ nach wie vor die Entwicklung von Medikamenten für seltene Krankheiten. Wir sind begeistert, dass auch die FDA (Food & Drug Association) unsere Arbeit unterstützt.

Schauen sie sich die Plenar-Präsentationen über „Getting Orphan Drugs to Market“ von Dr. Lewis Fermaglich, FDA, und Dr. Diana Wetmore, Harrington Discovery Institute an.

Unsere erste Diskussionsrunde über das Thema „Potential Therapies for FOXG1 Syndrome“ (Potenzielle Therapien für das FOXG1 Syndrom) wurde von Dr. Yael Weiss, Dr. Antonello Mallamaci, Dr. Soo Lee and Dr. Sylvain Lengacher gehalten. Die wichtigsten Erkenntnisse sind:

1. Quer durch das Spektrum der FOXG1 Mutationen können wir verschiedene Auswirkungen auf den Protein-Level, Astro-Entstehung (astrogenesis) und andere Aktivitäten im Gehirn erkennen. Dies muss nicht zu verschiedenen Therapien pro Mutation führen, aber es könnte Einfluss auf unterschiedliche Dosierungen und kombinierbare Vorgehensweisen haben.

2. Die ideale Therapie wäre, Mutationsdefekte zu bearbeiten, aber da die Off-TargetEffekte immer noch Besorgnis erregend sind (unsere Kinder bekommen z. Bsp. durch die Behandlung Gehirntumore), könnten Mikro-RNA ́s ein Weg sein, das FOXG1 Protein und andere Level im Gehirn zu modelieren. Wir sehen, dass Experimente erfolgversprechend sind, in denen die MikroRNA ́s die FOXG1 Protein-Level ansteigen lassen.

3. Wir können ebenfalls erkennen, dass eine FOXG1 Überexpression einen Phänotyp des FOXG1 Syndroms verursachen kann, dies wird untersucht, um uns beim Verständnis der Dosierung zu helfen.

4. Gliazellen und Gehirnmetabolismus sind innovative Zielscheiben für FOXG1 Syndrome. Präklinische Daten belegen, dass siRNA-vermittelte Runter-Regulierung von FOXG1 in Astrozyten den Gehirn-Energie-Metabolismus dramatisch beeinträchtigen und kleine Moleküle GP-57 als Medikamente dienen könnten, um dies zu bewerkstelligen.

5. Um FOXG1 Protein-Levels nicht zu überaktivieren und noch mehr Schaden anzurichten, kann eine kombinierte Einstellung wichtig sein. Es könnte sein, dass wir Neuronen und Astrozyten stimulieren müssen, aber wenn ein Zelltyp stimuliert wird, könnte das eine Auswirkung auf einen anderen Zelltyp haben, dem wiederum entgegengewirkt werden müsste.

Dr. Soo-Kyung Lee, Dr. David Bedwell und Dr. Chris Ahern präsentierten unser letztes Forum „Potential Therapies for Nonsense Mutations“ (Potenzielle Therapien für Nonsense Mutationen). 30% unserer Kinder haben Nonsense Mutationen und es ist extrem interessant, dass wir zwei potenzielle vielversprechende Therapien in Aussicht haben.

1. Die erste mögliche Therapie besteht aus so genannten “Readthrough” (durchlesen) Wirkstoff, erhöht die Proteinproduktion von FoxG1. Zur Zeit erproben wir diese Wirkstoffe an HEK Linien (Nierenzellen) und SH-SY5Y Zellen Neuroplastomazellen. Erfolgversprechende Wirkstoffe werden weiter in Stammzellen und Mausmodellen angewendet. Ein wichtiger Aspekt dieser Forschung ist die Dosis, die wir damit erreichen können für jede Mutation. Dafür braucht man die Information wieviel FoxG1 wird benötigt? An dieser essentiellen Frage wird momentan von den Wissenschaftlern nach der Antwort gesucht.

2. Die zweite mögliche Therapie beinhaltet die Reparatur vorn „Stop-Codons“, in dem eine tRNA Gen-Therapie genutzt wird. In dem Fall würde die tRNA Sequenz verändert werden um „Stop-Codons“ zu unterdrücken. Was wir in Erfahrung bringen konnten ist, dass wenn die Reparatur robust ist, 40-80% der Wildtyp- Expression erreicht werden können, was viel höher ist als ein “Readthrough” Wirkstoff je erreichen könnte. Obwohl dies vielversprechend klingt, müssen noch alle Aspekte, wie z. Bsp. das Verständnis ob tRNAs andere ungewollte Nebenwirkungen hat, getestet werden.

3. Das Ziel könnte wiederum kombinierbar sein – die Verwendung von tRNA und Schichtung auf Nonsense-Verbindungen für den effektivsten Ansatz für unsere Kinder, die von Nonsense-Mutationen betroffen sind.

Häufigkeit der Unterdrückung von Nonsense-Codons erhöhen.

Wir haben keine Zeit darauf verwendet über Gen-Therapien und Anti-Sense-Therapien für FOXG1 Syndrome zu sprechen. Diese sind in der ersten Phase und es gibt noch nicht genug Datenmaterial, über die man sprechen könnte. Wir hoffen, bei unserer nächsten Konferenz im Jahr 2021 ein solides Forum zu diesem Thema anbieten zu können.

Tag 2 endete mit zwei erfolgreichen und informativen Stunden in verschiedenen Breakout-Räumen mit Wissenschaftlern, Eltern und Pflegern. Der Austausch hätte noch stundenlang fortgeführt werden können und wir freuen uns darauf, noch weitere solche Diskussionen führen zu können.

In der Zwischenzeit werden wir alle Updates in diesem Blog und auf unserer FOXG1 Research Facebook Seite teilen.

Zu guter Letzt: 

Keine dieser Anstregungen ein Medikament zu finden, wäre ohne Spenden möglich. 80% unserer Arbeit beruht auf privaten Spenden und beinahe 100% der Spenden gehen in die Forschung. Bitte klicken Sie hier um zur Erforschung eines Medikaments für das FOXG1 Syndrom für eine bessere Zukunft unserer Kinder zu spenden. Vielen Dank! 

- Tina Kouemo-Burri 

The FOXG1 Science Symposium 2020 - Recap

On August 17th and 18th we held the FOXG1 Science Symposium 2020 as a virtual event rather than at the University at Buffalo as originally planned. While we missed the chance to gather together in person, the silver lining was an audience that far surpassed our expectations with more than 300 attendees. 

It was a truly remarkable event, with new and rich data and a growing consortium of scientists, industry executives, caregivers, and more all focused on the path to disease-modifying therapies for FOXG1 syndrome.

Much of the content, including Q&A sessions, is available to watch here. Please note that we’ve extracted most of the presentations due to sensitive unpublished data. 

I kicked off Day One with an overview of The FOXG1 Research Foundation’s singular goal: to find a cure for FOXG1 syndrome for all affected-children globally. We have come a long way since we started in September 2017!

Click on my Welcome to watch an overview of our strategy and research and our new machine-learning Natural History Study.

We pride ourselves from learning from the best rare disease group leaders. Click on the Day One Keynote to watch the presentation by Dr. Art Beaudet on the road taken to find a cure for Angelmans’ Syndrome. 

Our first panel, Clinical FOXG1 Syndrome Phenotypes, shared prepublished data from the FOXG1 Patient Registry that focuses on understanding the spectrum of FOXG1 phenotypes (symptoms) that children experience. We see slightly different symptoms depending on the specific genetic FOXG1 mutation (deletion, missense, etc). Parents on this panel spoke about medical symptoms, developmental symptoms, and behavioral issues that their children are facing. We have submitted a paper with this information for publication in scientific journals titled “Expanding genotype-phenotype correlations in FOXG1 syndrome resulting from a patient registry.”

The following leading clinicians and scientists have contributed to this study: Elise Brimble, MS, Kathryn G Reyes, BS, Orrin Devinsky, MD, Maura Ruzhnikov, MD, Xilma Ortiz-Gonzalez, MD, Ingrid Scheffer, MBBS, PhD, Nadia Bahi-Buisson, MD, PhD, Heather Olsen, MD, MS

We also heard from three different incredible FOXG1 parents whose children represent a spectrum of FOXG1 phenotypes. Greg Wells, Laura Patterson, and Stefani Miles each shared a presentation welcoming us into the lives of thier children. There is truly no greater resource to understand this syndrome than the children themselves. We were all so moved to get to know Ali, Emma, Bo, and Caleb.

Next, we heard from Dr. Soo-Kyung Lee, Dr. John Mason, Dr. Michael C. Yu and Dr. Priya Banerjee on the panel Basic FOXG1 Biology. We heard that the FOXG1 gene is expressed in different cell types in the brain, and the gene is conserved in most animals (most animals have a similar FOXG1 gene sequence to humans), thus we know we can use animal models as a platform to study FOXG1 biology.

Speakers discussed Protein Arginine Methylation and Liquid-Liquid Phase Separation as novel ways to understand FOXG1 gene biology in order to develop treatments. These treatments can help to control FOXG1 protein function. 

We then dove into the panel on FOXG1 Cellular Modeling and heard from Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri and Dr. Aparna Bhaduri.  

There were three main takeaways from this panel: 

1. The level of FOXG1 dosage is critical with clear evidence for different genes being regulated at different doses. This may help in better understanding the variable phenotypic outcome in patients. 

2. Patient organoid modeling is underway and promises to reveal exciting insights into patient-specific biology and enable drug screening. 

3. While organoids are a great resource for modeling the human brain, it’s important to carefully assess the health and differentiation status of the cell types of interest going forward and to make sure there is a healthy representation of what we are trying to model

Dr. Jessica Mariani replaced Dr. Vaccarino for the Q&A discussion, which you can watch here.

Our last panel of Day One defines a true “global conference” with scientists from Tokyo to Texas!  FOXG1 Animal Modeling featured Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi and Dr. Corinne Houart.

Early data was shared from the six heterozygous mouse models being developed and our heterozygous zebrafish models. The most important takeaway was early data establishing a clear phenotype (symptoms) from these models versus the control. This is important as it shows these animals will be excellent models for drug testing. This is the first step in drug testing, without a correct model we will not be able to screen anything. We also learned that we can target both the FOXG1 gene directly, as well as factors like excitatory/inhibitory neuronal imbalance. This is important as it gives multiple ways to rescue symptoms for our children. 

When we started the FOXG1 Research Foundation there was no concerted effort to invest in translational research for FOXG1 syndrome. The research, at that point, had been focused on the FOXG1 genes’ role in overall brain development. As a foundation, it is so important that we stay collaborative. Dr. Soo Kyung-Lee and Dr. Jae Lee are part of our FOXG1 family and we are blessed that they continue to engage deeply with all scientists and share their pre-published work. 

Today, we are getting closer to a cure. Over the next two years we will be screening drugs, gene therapies, antisense therapies, and more. One thing that has been made obvious is how complex the FOXG1 gene is, even though it is such a small gene, and how important it is to understand the biology of FOXG1 at a molecular and cellular level. 

This understanding of FOXG1 biology will lead to inventions and ideas. 

Our President, and co-founder Nicole Johnson kicked off Day Two with a personal story about her daughter, Josie and then set up the day’s focus on translational science.

The Day Two opening plenary session was centered on the drug development process for rare diseases. We want to avoid the “valley of death,” where academic ideas get stuck and never make it to market. Luckily the Orphan Disease Act continues to support the development of rare disease drugs. We are thrilled the FDA is so supportive of our work.

Watch the presentations on Getting Orphan Drugs to Market from Dr. Lewis Fermaglich of the FDA and Dr. Diana Wetmore from the Harrington Discovery Institute.

Our first panel on Potential Therapies for FOXG1 Syndrome featured Dr. Yael Weiss, Dr. Antonello Mallamaci, Dr. Soo Lee and Dr. Sylvain Lengacher. Key takeaways are:

1. Across the spectrum of FOXG1 mutations, we are seeing different impacts on protein level, astrogenesis and other activities in the brain. This doesn’t need to lead to different therapies per mutation, but it could lead to different dosage levels and combinatorial approaches.

2. The ideal therapy would be to gene edit mutation defects, but, since off-target effects are still too high of a concern (our children developing brain cancer from a treatment, for example), micro RNA’s could be a way to modulate FOXG1 protein and other levels in the brain. We are seeing success in experiments that microRNAs are increasing FOXG1 protein levels. 

3. We also see that FOXG1 overexpression can cause a FOXG1 syndrome phenotype and this is being studied to assist us in understanding dosage. 

4. Glial cells and brain metabolism are innovative targets for FOXG1 syndrome. Preclinical data shows that  siRNA-mediated down-regulation of FOXG1 in astrocytes dramatically affects brain energy metabolism and small molecule GP-57 could be a drug we use to accomplish this. 

5. In order not to over-activate FOXG1 protein levels and cause more damage, a combinatorial approach can be very important. We may need to stimulate neurons and astrocytes, but by stimulating one cell type we could have an impact on another that would need to be countered. 

As noted, we removed the presentations from the videos, but the panel discussions and Q&A with attendees is available to watch here.

Dr. Soo-Kyung Lee stayed online to moderate the final panel of the symposium with Dr. David Bedwell and Dr. Chris Ahern titled: Potential Therapies for Nonsense Mutations. 30% of our children have nonsense mutations and it is extremely exciting that we have two strong potential therapies on the horizon.

1. The first are readthrough compounds increasing frequency of nonsense codon suppression. We are currently screening this library on FOXG1 HEK293 (kidney cells) and SH-SY5Y (neuroblastoma cells) reporter cells. Successful hits will be further tested in patient derived nonsense stem cells and mouse models. One important aspect of this research is the percentage of suppression we can get by mutation. For this, we need information on how much FOXG1 protein is enough? This is a question our basic science researchers are working on. 

2. The second potential therapy involves repairing stop codons using tRNA gene therapy. Here, we would change the tRNA sequence to suppress stop codons. What we’ve learned is that if repair is robust, 40-80% of wildtype expression can be gained, which is much higher than what a readthrough compound could achieve. While this is exciting, we still need to test all aspects such as understanding if tRNA’s cause other unwanted effects. 

3. The goal may again be combinational - using both tRNA and layering on nonsense compounds for the most effective approach for our children with nonsense mutations

We did not spend time discussing gene therapy and antisense therapy efforts for FOXG1 syndrome. Those are in the preliminary phases and not enough data is present to share. At our next conference in 2021, we plan to have a robust panel on these therapeutic approaches. 

Day Two included two hours of engaging Breakout Rooms for scientists and for parents and caregivers. The conversations could have gone on for hours and we’re looking forward to hosting more of these types of discussions.  

In the meantime we will be sharing updates here on this blog and on our FOXG1 Research Facebook page

Last, none of this work to find a cure would be possible without donations. 80% of our work has been funded by personal donations, and nearly 100% of donations go towards research. Please click here to donate to find a cure for FOXG1 syndrome! We are all on this excting path to a cure together.

Written by Nasha Fitter, FOXG1 Research Foundation CEO, co-founder, and mom to Amara

FOXG1 Symposium Advances Science, Gives Hope to Families Battling Rare Disease

UB biological sciences faculty member Soo-Kyung Lee, left, and UB biological sciences researcher Younjung Park work in the lab. Photo: Douglas Levere

By CHARLOTTE HSU

Published August 20, 2020

UB biologists Soo-Kyung Lee and Jae Lee have devoted their careers to studying FOXG1 syndrome, a neurological disorder that affects their daughter, Yuna.

This month, as part of that work, the couple took part in the FOXG1 Science Symposium 2020, which brought researchers, industry executives and families together for two days of presentations and conversation about the latest scientific advancements tied to the disease.

The disorder, caused by mutations in a gene called FOXG1, can lead to severe abnormalities in brain development. When Yuna was younger, she suffered from many seizures and had trouble swallowing milk. Now, at 10 years old, the seizures have subsided and she is a joyful child, but she still cannot eat, walk or get dressed on her own.

“It is exciting to see how the FOXG1 community has grown worldwide and is coming together to support each other and FOXG1 research,” says Soo-Kyung, Empire Innovation Professor and Om P. Bahl Endowed Professor of Biological Sciences, College of Arts and Sciences.

UB biologists Soo-Kyung Lee (left) and Jae Lee are researching the FOXG1 gene. Their daughter, Yuna, has a mutation in the gene, which has severely impacted her development. Photo: Douglas Levere / University at Buffalo.

“This is our second FOXG1 science symposium. Our first symposium two years ago was really about basic science. This year, we’re really focused on answering the question of what we know about FOXG1 syndrome, and what the path forward is toward potential therapies,” says Nicole Johnson, president and co-founder of the FOXG1 Research Foundation, which organized the event and has funded the research of the Lees and other scientists. Johnson’s daughter, Josie, has FOXG1 syndrome.

The symposium — originally scheduled to take place at UB — was hosted virtually instead from Aug. 17-18. About 300 people attended.

Soo-Kyung and Jae, professor of biological sciences, presented on and moderated a number of panels on topics such as the biology of FOXG1 and efforts to develop animal models for the disease. Other UB presenters included Michael Yu, associate professor of biological sciences, and Priya Banerjee, assistant professor of biological sciences.

Yuna flashes a big smile as she plays with her father, Jae Lee, and mother, Soo-Kyung Lee (right), who both are biology researchers at UB. Photo: Douglas Levere

A growing FOXG1 community, and advancements in science

Johnson notes that while FOXG1 syndrome is a rare disease, the number of diagnosed cases is rising as genetic sequencing becomes more accessible, as FOXG1 has been added to several diagnosis panels, and as awareness of the disorder grows. Globally, the number of known patients has topped 700, according to the FOXG1 Research Foundation, which tracks cases through means such as a private social media group for families of children with FOXG1 mutations.

The growth of this community has given caregivers a support network. Soo-Kyung recalls that earlier this year, she and Jae received a message from a family in China with a baby girl who has FOXG1 syndrome, saying that they had enjoyed reading about the Lees’ research and Yuna’s progress.

“It is so heartwarming to know that someone out there finds comfort in our research efforts and is cheering for us,” Soo-Kyung says.

Prior to Yuna’s birth, Soo-Kyung’s lab focused on understanding the development of the central nervous system, with much of that work centering on transcription factors that regulate gene expression. Jae is also an expert on gene transcription. So when Yuna was diagnosed with FOXG1 syndrome, her parents were perfectly positioned to pivot and make FOXG1 the focal point of their work (FOXG1 is a transcription factor that plays a crucial role in development of the human brain.)

Together, the Lees are making discoveries about the functions of FOXG1, and breeding mice with FOXG1 mutations that mirror those found in human patients. The ultimate goal of their work is to develop a treatment: Though problems in early brain development cannot be reversed, a therapy could alleviate some symptoms.

“The symposium gave FOXG1 scientists around the world the chance to get together to share their work, with the potential to build collaborations,” Jae says.

For families who attended, “It’s very hopeful for parents to see so much work being done, and see different scientists really investing their entire work in FOXG1,” Johnson says. “It gives hope.”