The ORCA (Observer-Reported Communication Ability) outcome measure
In 2018, FAST funded Dr. Bryce Reeve of Duke University to create a novel communication measurement tool as an outcome measure assessment of caregiver observations of a child’s ability for expressive communication in nonverbal patients with complex communication needs like Angelman syndrome (AS). We are happy to announce that not only was Dr. Reeve successful in creating such a tool, but that it is being used by others in the Angelman space. This successful partnership and strong engagement with the Angelman community allowed the development of the Observer-Reported Communication Ability (ORCA) measure to be fast-tracked (<1.5 years from conception to having a measure).
In a FAST survey among its Facebook members, 332 parents/caregivers indicated one of the most important improvements they wanted to see in their child with AS was changes in their communication. In response, FAST made improvements in communication ability one of the key markers for effectiveness of therapies to be tested in clinical trials. However, there lacked good quality parent/caregiver-reported measures of communication ability that would provide a reliable and valid assessment for individuals with AS. Recognizing this limitation, the FAST organization partnered with the Center for Health Measurement (CHM) at Duke University School of Medicine to design and evaluate a measure with the goal to use the measure in clinical trials to detect change in communication ability over time.
As a result, CHM, in collaboration with FAST, designed the Observer-Reported Communication Ability measure with direct feedback and involvement from the AS community. FAST funded the creation of the ORCA as part of our Angelman Biomarker and Outcome Measure Initiative (ABOM) efforts. The purpose of the ABOM initiative is to create and/or identify biomarkers and outcome measures to be used in a pre-competitive spirit, non-proprietary manner across all parties’ interest in developing therapeutics for Angelman syndrome. One of FAST’s goals in funding Dr. Reeve’s grant was to provide this valuable tool for researchers within the Angelman space, as well as for other disorders.
The ORCA measure includes 72 questions that capture various types of expressive, receptive, and pragmatic forms of communication and is able to place each individual with AS along a continuum of communication ability that allows for examination of their changes over time. The ORCA does not rely on speech, but allows gestures, vocalizations, and use of aids to capture communication ability. It takes about 15-20 minutes for a parent/caregiver to complete the measure independently without the help of a clinician or speech language pathologist.
The ORCA measure was designed following best practice recommendations by the U.S. Food and Drug Administration (FDA) and other organizations. First, the CHM team conducted in-depth interviews with both caregivers of individuals with AS and communication experts with experience working with individuals with AS to identify relevant types of communication behaviors. From these interviews, the CHM team learned of 22 communication concepts that were important to include on the ORCA measure such as seeking attention, requesting “more” of something (e.g., food), making choices, and greeting people. Second, the CHM team conducted additional interviews with caregivers of individuals with AS to make sure the questions included in ORCA were understandable and appropriate. Third, the CHM team collected responses to the ORCA questionnaire from 290 caregivers/parents of individuals with AS. With this data, the CHM was able to find strong evidence for both the reliability and validity of the ORCA measure to capture communication ability. All these steps are currently being written-up by the CHM team and FAST representatives and will be published in the scientific literature and shared with the FDA.
The ORCA measure is now being used in clinical trials and natural history studies for individuals with AS. Additionally, the CHM team is working to translate the English version of the ORCA into other languages so it may be used globally. Also, the ORCA measure may be used in other conditions/disorders that have significant communication deficits.
Dr. Reeve is the Director for the Center for Health Measurement, as well as a Professor of Population Health Sciences and Pediatrics within the Duke University School of Medicine. Dr. Reeve is an internationally recognized psychometrician. Dr. Reeve’s areas of expertise include developing patient-reported questionnaires using qualitative and quantitative methodologies and the integration of patient-reported data in research and healthcare delivery to inform decision-making.
FAST Awards Drs. Silverman (UC-Davis) and Duis (Children’s Hospital Colorado) Grant to Study Gait as an Outcome Measure for Angelman Syndrome
Movement disorders affect nearly all individuals with Angelman syndrome (AS), with the most common concerns being spasticity, ataxia (as observed in the majority of ambulatory individuals), tremor, and muscle weakness. Clinically, over time, individuals may develop a crouched gait which can cause a progressive decline in mobility. Similar motor disorders are observed in Angelman syndrome rodent models; dysfunction on the rotarod and reduced activity have been consistently reported in AS rodents. Under this grant, this translational research will explore various aspects of gait across different age groups and will be assessed and compared from both a non-clinical (rodent) and clinical (human) perspective.
Current patient mobility tests such as the 6-minute walking test or the 4-stair climbing test are inaccurate, lack rigor and reproducibility because they are highly dependent on patient motivation at the time of assessment and are not granular enough to discover quality changes in gait over time. They represent a single time point evaluation in a controlled environment, where the patients must travel to be assessed. Functional assessments are often not representative of a skill set when a patient is in their own environment. In addition, there is associated anxiety in unfamiliar environments for both the patient and the caregiver. Knowing that an individual will perform most accurately in a familiar environment, utilizing a measure that can be applied in that setting is ideal.
Current mobility tests in humans and rodents can be inaccurate, or not translatable; therefore, improved motor-based outcomes that can be assessed across species for gross motor skills, fine motor skills, and gait quality, require further dedicated research and resources. Drs. Duis and Silverman have narrowed down and developed several outcome assessments that can be utilized in parallel across both rodents and humans. This grant focuses on various spatial and temporal aspects of gait as an outcome measure in both preclinical (rodent) and clinical (human) research models, and will assess how that changes across developmental ages.
This study will test the production and accuracy of sensor-based technology in individuals with AS across all genetic subtypes (deletion, UPD, ICD, UBE3A mutation), as well as AS rodents in relationship to gross and fine motor markers. Dr. Duis will recruit 40 individuals with AS for the clinical half of the study. Drs. Duis and Silverman will utilize cutting edge sensor-based technology such as DigiGATE, ActiMyo® (using wearable brace-anklets to collect a wide variety of motor metrics), gait laboratory assessments via treadmills and 3D motion, and Zeno walkway. Drs. Silverman and Duis will also identify spatial and temporal parameters in the Ube3a mouse and the FAST Ube3a rat model. The information developed through this grant will provide truly translational outcome measures to test therapeutics across age groups in both rodent and human, with the goal of expediating its utility for human clinical trials.
By increasing the number of relevant, innovative, in vivo functional outcome measures in our wheelhouse, we will create more opportunities for identifying and moving forward successful medical interventions where we have accurate ways to assess motor improvements over time.
FAST update on the impact of Covid-19
While the world as we know it has changed, abruptly and dramatically, we at FAST want you to know that we are here and we continue to move forward in our mission to cure Angelman syndrome.
What COVID-19 precautions should parents of children with Angelman syndrome be taking?
Although individuals with Angelman syndrome are not known to be in the Center for Disease Control defined higher risk categories, the concerns about infection are always heightened in our community. In addition to the preventive measures we are all now very much aware of (washing hands, social distancing, disinfecting, etc.), here are a few resources you may find helpful:
How do school closures affect our children with Angelman syndrome?
We realize that as a community, our kids being home from school is more complicated than it is for their neurotypical peers. Most of our children with Angelman syndrome have IEPs (Individualized Educational Plans) which makes distance learning much more challenging. Without any formal training, we are now acting as educators, para-educators, therapists, social workers, and behaviorists. If you haven’t already done so, reach out to your child’s educational team to request a tele-consult for guidance on your child’s unique needs.
FAST advises all of us to take a deep breath, be kind to ourselves, be patient, and check out some of these helpful resources:
- Wrightslaw’s guidance on Coronavirus and Your Child’s Special Education
- FAST’s Educational Summit Videos
- FAST board member Kelly David has compiled this awesome list of homeschooling resources.
What local resources are available for support?
FAST has complied a list of potential resources for families within the United States that may be faced with hardship or are searching for local resources.
What is happening with FAST-funded research?
FAST has recently approved funding for three novel research projects and have several additional research contracts in process. We realize that the state mandated closures will most likely delay progress in the labs; however, as soon as restrictions are lifted, our researchers are ready, excited, and anxious to get back to the work of developing therapeutics to treat all individuals with Angelman syndrome. FAST will be sharing summaries of our exciting new research projects and our new caregiver support initiatives soon, so stay tuned!
What is happening with the GeneTx Biotherapeutics’ clinical trial?
Scott Stromatt, M.D., CMO of GeneTx Biotherapeutics provided the following update,
“The first group of patients in the clinical trial of GTX-102 have received their first dose. The clinical trial is proceeding as planned and we are closely monitoring the COVID-19 pandemic and how it might impact this clinical study. Patient safety is paramount and we are making adjustments as necessary to continue the required monitoring while reducing the burden to families where possible. The FDA has also recognized the need for flexibility for patients in clinical trials and issued a document to help companies implement changes to studies in-tended to help protect patients during this difficult time. One site is activated and treating patients, while the other six sites are in various stages of the activation process. The pandemic has slowed down the site activation process as each institution is addressing the COVID-19 pandemic in their region.”
What is happening with Ovid Therapeutic’s Angelman Trials?
Ovid clinical trials are continuing. We are closely monitoring COVID-19 and the evolving impact on families in our clinical trials. Every location where our clinical trials are being conducted faces different challenges and disruptions, so it is crucial that families and site study teams remain in close contact. Ovid is in regular contact with each site to provide guidance. In the event you lose contact with your study team, please contact Ovid and we will provide immediate support.
Currently, Ovid has two ongoing clinical trials in Angelman syndrome: The Phase 3 NEPTUNE study, and the Open-Label ELARA study. Both of these clinical trials are proceeding. The safety of every member of the Angelman community is the core focus for Ovid during this global crisis, and we plan to proceed with empathy, integrity and responsibility.
What is happening with the Angelman Natural History Trial?
As you are probably aware, all of the institutions that are involved in the ongoing Angelman Syndrome Natural History study have suspended non-urgent clinical operations, including all elective surgeries, clinic visits, and research visits, until the pandemic is under control and the physical distancing recommendations are lifted. While we hope that research visits can be conducted again from May-June 2020 onwards, no one knows when normal operations will resume at each institution.
We greatly appreciate your ongoing support of our study. The health and safety of our families is paramount, so we will not be having in-person visits until it is safe to do so again. We plan to continue with the Angelman Syndrome Natural History study by completing the questionnaires and standardized assessments that can be performed remotely via telephone calls, Skype, Zoom, or other means.
What is happening with the Freesias Study?
We understand those living with Angelman Syndrome and their loved ones may be facing a high level of uncertainty during this serious health situation. Patient safety is Roche/Genentech’s highest priority. As a company, we are taking COVID-19 seriously and are committed to keeping the communities we serve updated with any new information we learn that could help inform health decisions related to our medicines and clinical trials.
Roche/Genentech are taking the necessary cautionary measures and working to keep specific home based FREESIAS activities on-going for patients and families. However, site visits and home visits are all paused at the time.
- What activities can continue:
- Sleep mat
- Sleep diary
- Seizure diary
- What activities have paused:
- Site visits
- Home visits (EEG/PSG)
- Actigraphy around home visits
Any questions that you have around FREESIAS or how Covid-19 impacts the timeline, can be directed to your specific study site coordinator. Please stay well and healthy and we will continue to update the community and FREESIAS sites as information around Covid-19 evolves.
What is happening with the IONIS trial?
As the COVID-19 pandemic evolves, our main concerns are you and your health. While we continue to focus on advancing our programs which includes planning for the phase 1/2 study in Angelman Syndrome patients, we are cognizant of the strain this pandemic puts on our healthcare systems.
Ionis is carefully monitoring the situation and focused on the safety of our study participants. For patients already enrolled in clinical trials, we advise patients and families participating in our clinical studies to follow the advice provided by their clinical trial site team and abide by any guidance issued by local authorities. For our upcoming clinical trial in AS, our priority is to keep the program on track and maintain our current timeline to start the study in the fall, while maintaining the safety of everyone involved.
What about fundraising events?
Our community members that are holding grassroots fundraising events in the immediate future are evaluating, on a case by case basis, whether their event needs to be postponed or cancelled. Although promoting your CAN page during these trying times meets the social distancing criteria, we understand that fundraising is difficult due to the economic uncertainty we all currently face. We do suggest keeping your network of supporters updated, via your CAN pages, on exciting developments in the Angelman community so that when these difficult times are behind us, we can once again count on their robust support to assist us in curing Angelman syndrome. FAST is thrilled to still be receiving donations daily and as al-ways, we are extremely grateful to our community who supports us in both good times and bad.
What about the 2020 FAST Summit & Gala?
While we do not know what the future holds, we will continue to move forward with our plans to hold the 2020 FAST Summit & Gala and are praying that it is the grand celebration we will all desperately need by that time. FAST will roll out the 2020 FAST Summit & Gala Ticket Giveaway and Scholarship Applications as normally planned, making any modifications as necessary, and will keep our community up to date at every step along the way.
We do not know how long or how vast the impact of COVID-19 will be; however, be certain, that we will continue to do our best to CureAngelmanNow! We at FAST are grateful to each one of you, for raising awareness, raising funds, being there for each other and truly, being One Committed CommUNITY!
If you have additional questions that have not been addressed in this statement, please contact us at info@CureAngelman.org.
Local Resources
FAST has complied a list of potential resources for families within the United States that may be faced with hardship or are searching for local resources. The following links may be useful for finding financial support, helping with food insecurity, and other needs at this time.
- NORD launched the Financial Assistance Program for Rare Disease Community Members that are affected by COVID-19. This program is meant to support members of the rare disease community with financial relief for critical non-medical needs. https://rarediseases.org/nord-launches-financial-assistance-program-for-rare-disease-community-members-impacted-by-covid-19/
- 211 provides individuals with locally curated social services within the United States and Canada. 211 can provide information as well as referrals.
http://211.org - Findhelp connects individuals seeking help with a network of verified (by Findhelp) social care providers.
http://findhelp.org - Grantspace provides a list of possible resources to assist with the financial hardships of COVID-19.
https://grantspace.org/resources/knowledge-base/covid-19-emergency-financial-resources/#anchor1
The information and links provided above are for general informational purposes only. In accessing these sites, you are leaving the www.CureAngelman.org website. These links are offered only for use at your discretion. All information and links are provided in good faith; however, by providing links to other sites, FAST does not guarantee, approve or endorse the information or products available on these sites.
FAST funds pioneering infrastructure grant
FAST is thrilled to announce a grant to our continued partners and renowned scientists dedicated to advancing therapeutics for Angelman syndrome – David Segal, Ph.D., Jill Silverman, Ph.D., and the team at the University of California, Davis. This grant provides the funding to build a lab devoted to Angelman syndrome (AS) research, establishing an infrastructure in which this team can evaluate multiple therapeutics simultaneously.
Dr. Jill Silverman is a behavioral neuroscientist with 18 years of training and experience focusing on preclinical rodent model systems with a strong emphasis in neurodevelopmental disorders and intellectual disability.
Dr. David Segal is a UC Davis professor of Biochemistry and Molecular Medicine with joint appointments in the Genome Center, the MIND Institute, and the Department of Pharmacology. His area of expertise is in gene editing.
This funding will:
- Create a stable infrastructure for rapid testing of potential therapeutics in AS rodent models through at least 2025
- Train and retain staff dedicated to these studies, creating a new generation of scientists focused on AS research with combined expertise in molecular and behavioral components of AS
- Provide lab equipment and supplies
- Maintain AS cell lines and rodent model colonies at the University
- Provide long term stability for this dedicated team to keep their focus on identifying and evaluating potential therapeutics for the treatment of Angelman syndrome
Drug evaluation is incredibly complex as various animal models and cell lines need to be carefully and thoroughly evaluated in order to gain accurate conclusions. This team has dedicated their careers to perfecting this task, and have become key opinion leaders in understanding Angelman syndrome specific models. Dr. Silverman has developed the experimental design, in collaboration with Dr. Segal, validated and standardized testing procedures, and will oversee all aspects of results interpretation. Dr. Segal will direct the molecular analysis of the experiments. They bring with them an impressive team of geneticists and researchers with vast experience in working with disease specific models. This program will allow external researchers and industry partners to have access to this wealth of expertise.
There are multiple pharmaceutical companies that have potentially promising therapeutics for the treatment of AS. However, they do not have expertise in AS, or the specific tools necessary to properly evaluate these drugs for this population. This infrastructure grant allows AS experts to provide those services and elucidate if a potential therapeutic warrants further development toward potential human clinical trials.
As examples, two new projects are currently being sent to this UC Davis team:
- Evaluation of a small molecule in Angelman rodent models that was recently reported to rescue deficits in motor function and learning in an adult AS mouse model. The lab will seek to independently validate these reports in mice and rats.
- Screening of a new drug library in AS reporter neurons. These compounds will be evaluated in primary neuronal cultures and carefully evaluate for paternal Ube3a gene activation.
FAST is incredibly hopeful about therapeutics already in and nearing human clinical trials. But we are not finished until every person with Angelman syndrome sees a meaningful therapeutic benefit. We keep pushing, and this lab with these amazing individuals will be part of what enables us to do this even more efficiently and effectively.
Publicación de la investigación innovadora detrás del descubrimiento de GTX-102 para el síndrome de Angelman
The decades-long work conducted at Texas A&M was featured in the March 2023 issue of Science Translational Research
Un artículo recientemente publicado en Science Translational Research destaca el trabajo dirigido por el miembro de la facultad de la Universidad de Texas A&M e investigador de Ultragenyx, el Dr. Scott Dindot y su equipo sobre la biología del síndrome de Angelman (AS) y el descubrimiento de una nueva terapia en investigación. En el artículo, el Dr. Dindot y sus coautores describen la investigación que se llevó a cabo para identificar la región óptima a la que apuntar en el gen responsable de SA y el desarrollo de GTX-102, que actualmente se evalúa en un estudio clínico de fase 1/2. GTX-102 es el primer tratamiento potencial para el síndrome de Angelman que alcanza esta etapa de desarrollo clínico y, si se aprueba, se convertiría en el primer tratamiento para la causa genética subyacente de esta devastadora enfermedad rara.
En el futuro, nuestra investigación y hallazgos no solo son prometedores para SA, sino que también brindan un camino a seguir para desarrollar terapias ASO para otros trastornos genéticos.
“En el futuro, nuestra investigación y hallazgos no solo son prometedores para SA, sino que también brindan un camino a seguir para desarrollar terapias ASO para otros trastornos genéticos”, dijo el Dr. Dindot.
Puedes encontrar más información sobre la historia completa de cómo GTX-102 pasó del concepto a la clínica en nuestro blog aquí.
Para obtener más información sobre la publicación de esta semana, consulta el comunicado de prensa completo de la Universidad de Texas A&M a continuación.
Carolyn Wang es vicepresidenta sénior de comunicaciones corporativas globales en Ultragenyx
Comunicado de prensa: Investigadores de Texas A&M detallan el innovador desarrollo del síndrome de Angelman
Una nueva publicación explica la ciencia novedosa detrás de la primera terapia molecular para el raro trastorno neurogenético que avanza hacia el desarrollo clínico
22 de marzo de 2023
Investigadores de la Universidad de Texas A&M han desarrollado la primera terapia molecular para el síndrome de Angelman que avanza hacia el desarrollo clínico.
En un nuevo artículo, publicado en Science Translational Medicine, el Dr. Scott Dindot, profesor asociado y miembro de EDGES en el Departamento de Patobiología Veterinaria de la Facultad de Medicina Veterinaria y Ciencias Biomédicas de Texas A&M (VMBS), y su equipo comparten el proceso a través de que desarrollaron este novedoso candidato terapéutico, también conocido como 4.4.PS.L, o GTX-102. Dindot también es director ejecutivo de genética molecular en Ultragenyx, que lidera el desarrollo de GTX-102.
El síndrome de Angelman (SA) es un trastorno neurogenético raro y devastador que afecta aproximadamente a 1 de cada 15 000 nacidos vivos al año; el trastorno se desencadena por una pérdida de la función del gen materno UBE3A en el cerebro, lo que provoca un retraso en el desarrollo, ausencia del habla, trastorno del movimiento o del equilibrio y convulsiones.
No existen terapias aprobadas para AS, y el estándar de atención actual se centra en la terapia conductual y el control de síntomas específicos, específicamente las convulsiones que a menudo afectan a los pacientes con AS.
En individuos sanos, la copia del gen UBE3A heredado de la madre se expresa en el cerebro y la copia del gen UBE3A heredado del padre es desactivada por otro gen, llamado transcrito antisentido UBE3A (UBE3A-AS).
Las personas que viven con AS tienen mutaciones que afectan la expresión o función de la copia materna de UBE3A y, como resultado, carecen de la proteína UBE3A en su cerebro. Dindot y su equipo comenzaron su investigación buscando una manera de prevenir el silenciamiento del gen UBE3A paterno y reactivar la expresión de la proteína deficiente.
En su investigación, Dindot y su equipo utilizaron diferentes enfoques genómicos para comprender cómo se regula la transcripción UBE3A-AS en el cerebro. Su trabajo descubrió una región previamente desconocida en UBE3A-AS que creen que representa el origen ancestral del gen en los mamíferos. También creen que esta región juega un papel clave en la regulación de la expresión de UBE3A-AS.
“Partes de esta región se han mantenido sin cambios durante más de 30 millones de años”, dijo Dindot. “La transcripción UBE3A-AS es un gen increíblemente complejo. Qué es y cómo se regula se ha debatido durante años”.
Luego, el equipo desarrolló oligonucleótidos antisentido (ASO), pequeñas moléculas sintéticas que comprenden ADN y ARN, para apuntar a la región conservada en la transcripción UBE3A-AS. Los medicamentos ASO funcionan uniéndose a un ARN objetivo y cortándolo, lo que hace que el gen deje de producir el ARN.
El equipo descubrió que los ASO que se dirigían a la región conservada desactivaron efectivamente UBE3A-AS, lo que, a su vez, reactivó la expresión del alelo paterno UBE3A. Los estudios muestran que los ASO reactivaron la expresión del alelo paterno UBE3A y aumentaron la proteína UBE3A en neuronas cultivadas de individuos con AS.
Como resultado de esta investigación, Dindot desarrolló el compuesto líder denominado GTX-102, que ahora se encuentra en desarrollo clínico.
“Usamos un enfoque novedoso para diseñar los ASO, apuntando a una parte muy específica de un gen en lugar de simplemente administrar un medicamento para tratar un síntoma”, dijo Dindot. “En teoría, este tratamiento va tras el corazón de la condición”.
Los datos provisionales de un ensayo clínico de fase 1/2 de GTX-102 en los Estados Unidos, el Reino Unido y Canadá indicaron previamente que el compuesto ha demostrado una “mejoría significativa” en pacientes pediátricos que padecen AS.
“En el futuro, nuestra investigación y hallazgos no solo son prometedores para AS, sino que también brindan un camino a seguir para desarrollar terapias ASO para otros trastornos genéticos”, dijo Dindot.
FAST anuncia una donación de 5 millones de dólares para acelerar los ensayos clínicos para el síndrome de Angelman y otros trastornos raros del neurodesarrollo
El centro universitario RUSH será dirigido por la Dra. Elizabeth Berry-Kravis.
FAST acaba de anunciar una donación de $5 millones para establecer el nuevo ensayo clínico y el esfuerzo de investigación traslacional para los trastornos raros del neurodesarrollo, el primer centro insignia de su tipo que será dirigido por la Dra. Elizabeth Berry-Kravis. Se conoce con el nombre de RUSH F.A.S.T. Center for Translational Research, y será la sede mundial para capacitar a las personas sobre la realización ensayos clínicos neurogenéticos y brindar terapias de intervención innovadoras que requieren métodos de administración novedosos y atención especializada.
Muchos de los médicos que trabajan en trastornos neurogenéticos están dirigiendo excelentes clínicas de atención general y especializada para subconjuntos específicos de trastornos, pero no están capacitados en las dificultades de establecer, ejecutar e informar sobre ensayos clínicos, lo que implica en una ausencia de capacitación específica para acelerar la ejecución de ensayos, lo cual está limitando significativamente la capacidad de inscripción en ensayos.
“Este es el amanecer de una nueva era. Hoy en día, hay más de 25 programas terapéuticos en proceso de desarrollo para el síndrome de Angelman, la mayoría financiados sólidamente por FAST”, dijo la Dra. Allyson Berent, directora científica de FAST. “Estamos en un punto de inflexión, en el que estamos listos para que muchos de estos programas lleguen a pacientes humanos para realizar ensayos clínicos en humanos en etapas tempranas, pero la mayoría de los centros hospitalarios no tienen el ancho de banda para mantenerse al día con esta necesidad explosiva.”
Para responder a esta necesidad, el nuevo centro, bajo la dirección del Dr. Berry-Kravis, quien ha estado al frente de ensayos clínicos durante más de 20 años, será el primer programa de capacitación organizado para personas que se centre en la ejecución de ensayos clínicos y la administración de fármacos novedosos para enfermedades raras y trastornos neurogenéticos. Al establecer un programa formal de becas para candidatos nacionales e internacionales, los médicos estarán capacitados para: comprender los pasos necesarios para incorporarse a un ensayo clínico prospectivo; los obstáculos normativos necesarios para aprobar contratos y aprobaciones éticas; desafíos en la configuración de la infraestructura para las pruebas de los pacientes y la formación de los equipos clínicos especializados necesarios para estos ensayos (por ejemplo, anestesia, coordinadores de ensayos, neuropsicólogos capacitados, neurólogos/epileptólogos, neurocirujanos y cualquier otro especialista relevante para un ensayo específico), y mucho más. Además, este programa respaldará la infraestructura y la construcción necesarias para crear una instalación de última generación en RUSH, con espacio para ensayos clínicos construido en torno a las necesidades de esta población de pacientes única.
Este centro de ensayos FAST pondrá todas estas piezas bajo un mismo techo como modelo de cómo ejecutar un ensayo clínico de la manera más eficiente y efectiva, lo que permitirá a la Dra. Berry-Kravis compartir formalmente su experiencia con otros y ayudar a aumentar las capacidades en docenas de centros adicionales a nivel mundial. Cuando un becario FAST complete su formación, podrá llevar esta experiencia a otras instituciones de todo el mundo. Para respaldar esto, FAST se compromete a respaldar financieramente la actualización de los centros de ensayos clínicos actuales y el establecimiento de nuevos, para aprovechar esta experiencia y garantizar que las capacidades de numerosos centros puedan satisfacer la gran demanda.
Los becarios de FAST tendrán capacitación práctica y se integrarán en el Centro durante un año completo, centrándose por completo en realizar ensayos clínicos para NDD. Además de los becarios, el centro RUSH F.A.S.T. también capacitará a los internos en períodos más cortos para aprender sobre la administración de medicamentos, mejorar sus propios conjuntos de habilidades y capacitarse en eficiencias para traer de vuelta a sus propias instituciones para administrar mejor la terapia intervencionista a más pacientes de la manera más segura y eficiente.
“Estamos en la cúspide de tantos avances vitales, por lo que es un honor ser nombrada directora del centro RUSH F.A.S.T. en un momento tan crítico” afirmó la Dra. Elizabeth Berry-Kravis. “Esto va a ayudar a muchas personas, y espero trabajar con las mentes más brillantes en el campo para generar los avances médicos del mañana”.
Nuevo estudio de UC Davis informa de rescate conductual en un modelo de ratón con síndrome de Angelman
Esta semana destacamos una publicación emocionante que surgió de la investigación financiada por FAST de los Dres. Dave Segal, Jill Silverman y Kyle Fink de la Universidad de California, Davis, informaron un rescate conductual en un modelo de ratón adulto con síndrome de Angelman después de la administración de un factor de transcripción artificial (ATF) con dedos de zinc dirigido al transcrito antisentido largo no codificante (Ube3a -ATS) que normalmente silencia la expresión paterna de Ube3a. Este es un enfoque de “detener la parada”.
Como recordatorio rápido, todo el mundo tiene una copia de UBE3A tanto la madre (materna) como del padre (paterna) en el cerebro y la copia paterna normalmente se silencia debido a una larga porción de ARN llamada transcripción antisentido (UBE3A-ATS). Esta transcripción UBE3A-AS normalmente está diseñada para unirse a la copia del padre y evita la producción de proteína UBE3A paterna a través del fenómeno de silenciamiento llamado “impresión”. Esto está bien cuando la copia materna puede producir UBE3A funcional, ya que solo se necesita una copia en las neuronas del cerebro, pero en el caso del síndrome de Angelman, donde el gen UBE3A materno no produce la proteína UBE3A, un enfoque prometedor radica en activar , o reactivando, el UBE3A paterno al desilenciar la copia paterna del gen.
Un factor de transcripción artificial (ATF) de dedo de zinc es una proteína diseñada que se une a una secuencia específica en el genoma y modula (cambia) la expresión génica. Este está diseñado para un objetivo específico, y en este caso fue diseñado para que el UBE3A-ATS “pare el tope” y active la copia paterna del gen UBE3A.
La creación de estos factores de transcripción artificiales requiere grandes esfuerzos de purificación y la proteína se degrada rápidamente (se agota) en el cuerpo, por lo que, en este artículo publicado recientemente, pudieron empaquetar el factor de transcripción en un vector viral AAV para una administración de dosis única.
Después de una dosis única del factor de transcripción artificial empaquetado en el AAV, que luego se administró a ratones adultos jóvenes, pudieron observar una reducción en el Ube3a-ATS y un aumento en la expresión de la proteína Ube3a en todo el cerebro del ratón. El tratamiento fue bien tolerado sin una respuesta inmune significativa. Sorprendentemente, el tratamiento mejoró las habilidades motoras en los ratones que lo recibieron, incluida la actividad general, el aprendizaje motor, el equilibrio/coordinación y las métricas de la marcha. Este es un nuevo estudio emocionante que respalda nuestro enfoque del Pilar 2 que se enfoca en otra estrategia de reactivación paterna, alineándose aún más con la idea de que el tratamiento en puntos de desarrollo posteriores (en este caso, ratones tratados con adultos) puede mostrar mejoras significativas en los resultados de comportamiento relacionados con AS .
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PILAR 3 — Dianas terapéuticas
Desde la fundación FAST a nivel internacional hemos definido un ROADMAP a la CURA 2.0. Este ROADMAP a la CURA 2.0 está compuesto de 4 pilares básicos que lo sustentan.
- PILAR 1 — Arreglar el gen materno.
- PILAR 2 — Activar el gen paterno.
- PILAR 3 — Dianas terapéuticas.
- PILAR 4 — Acelerar y preparar los ensayos clínicos.
Desgranemos juntos el tercer pilar básico hacia la CURA.
El pilar 3 del ROADMAP hacia la CURA2.0 consta de programas terapéuticos que se centran en “dianas terapéuticas para tratar los síntomas” al abordar diferentes vías moleculares y proteínas afectadas por la carencia de proteína UBE3A.
Actualmente, tenemos cuatro programas en preparación bajo el Pilar 3 (un ensayo clínico concluido y dos ensayos clínicos en humanos en activo):
- Suplementos de cetonas exógenas
Propósito: uso de cetonas exógenas para inducir la cetosis como una forma de controlar las convulsiones.
Empresa: Nutrición Disruptiva.
Ensayo clínico finalizado.
- Modulador alostérico positivo GABAaɑ5 (Alogabat)
Propósito: restaurar la señalización GABAérgica deficiente como una forma de mejorar las convulsiones y/o la cognición.
Mira la presentación de la Cumbre de Ciencias 2022 de la Dra. Brenda Vincenzi para obtener más información https://www.youtube.com/watch?v=hSuyj5Ku6WQ.
Empresa: Roche.
Todavía no se está reclutando para el ensayo clínico; más detalles:
https://clinicaltrials.gov/ct2/show/NCT05630066?cond=Angelman+Syndrome&draw=2&rank=9.
- IGF-1, 2 ligandos (NNZ-2591)
Propósito: regular la disponibilidad de IGF-1 y 2 para corregir la sinaptopatía observada en personas con síndrome de Angelman.
Mira la presentación de la Cumbre de Ciencias 2022 de la Dra. Nancy Jones para obtener más información https://www.youtube.com/watch?v=elnAwXypssk.
Empresa: Farmacéutica Neuren.
Reclutamiento de ensayos clínicos actualmente: más detalles https://clinicaltrials.gov/ct2/show/NCT05011851?cond=Angelman+Syndrome&draw=2&rank=4.
- BDNF
Propósito: utilizar un objetivo diana terapéutica de UBE3A capaz de regular los déficits de aprendizaje y memoria.
Institución: Universidad de Brown.
PILAR 2: ACTIVAR EL GEN PATERNO
Desde la fundación FAST a nivel internacional hemos definido un ROADMAP a la CURA 2.0. Este ROADMAP a la CURA 2.0 está compuesto de 4 pilares básicos que lo sustentan.
- PILAR 1 — Arreglar el gen materno.
- PILAR 2 — Activar el gen paterno.
- PILAR 3 — Dianas terapéuticas.
- PILAR 4 — Acelerar y preparar los ensayos clínicos.
Desgranemos juntos el segundo pilar básico hacia la CURA.
El pilar 2 del ROADMAP a la CURA 2.0 consiste en programas terapéuticos enfocados en “activar el gen de papá” tratando de activar en las neuronas la copia paterna silenciada del gen UBE3A.
Actualmente, tenemos 4 programas en trámite bajo el Pilar 2:
- Oligonucleótidos antisentido/Ácidos nucleicos esféricos (ASO/SNA):
Utiliza una combinación de ARN y ADN sintéticos para unirse al ARN del UBE3A-ATS (transcrito antisentido de UBE3A), que es el responsable de silenciar la copia paterna del gen UBE3A en las neuronas.
- Repeticiones palindrómicas cortas agrupadas regularmente interespaciadas (CRISPR)
Consta de dos componentes:
- La enzima CAS que es capaz de cortar:
- ADN (CAS o proteína asociada a CRISPR9) o,
- ARN (CAS13).
- Así como una guía de ARN (gRNA) que puede reconocer secuencias específicas de ADN o ARN para cortar
Esta tecnología a menudo se entrega a través de un vector AAV (virus adenoasociado), pero la nueva tecnología está avanzando para ofrecer opciones que no precisen de virus.
- Factores de Transcripción Artificial / Dedos de Zinc (ATF)
Una proteína que se une a la molécula UBE3A-ATS (transcrita y silenciada) provocando el desilenciamiento del gen UBE3A paterno.
- ARN de horquilla corta/micro-ARN (shRNA)
Piezas de ARN que se entregan en un virus AAV que se unen a la molécula UBE3A-ATS (transcrita y silenciada) y que activan la copia paterna silenciada del gen UBE3A en las neuronas.
Dentro del Pilar 2, tenemos 3 ensayos clínicos activos en humanos (GeneTX/Ultragenix, Roche e IONIS), ¡todos los cuales están dentro del programa ASO!