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.
Festival de música solidario a beneficio de ASA y FAST
Solo faltan 2 días para que los amantes del flamenco podamos disfrutar de un concierto solidario en el que el Síndrome de Angelman será protagonista.
Todos los beneficios van destinados a las 2 instituciones que trabajan por el SA en nuestro país: nosotros mismos @fast_spain, y nuestros compañeros de la Asociación del Síndrome de Angelman (ASA) @asociacion_sindrome_d_angelman.
¿Cómo puedes conseguir tu entrada?
Acudiendo en Gerena a los establecimientos autorizados: Centro TAS, Centro Gabinete Crea, Casa Pedro, Droguería-Ferretería Juanita.
Llamando al teléfono 661 09 81 62.
En taquilla, en el caso de que haya disponibilidad.
Precio:
Adultos: 10€
Niños/as hasta 12 años: gratis. Pero igualmente deben reservar su entrada, pues el aforo es limitado.
¿Y qué puedes hacer en caso de querer colaborar pero no poder asistir? Tenemos fila 0 para que hagas tu aportación:
Bizum: 02637
Número de cuenta: ES04 2103 4494 4400 3000 1573
O en la campaña de recaudación de fondos (CAN) que más te guste: https://www.cureangelman.es/can
Y además, habrá talleres para los más peques de la casa 
y servicio de bar 
¡Te esperamos! Porque sabemos que no te lo quieres perder.
RECUERDA:
25 de Noviembre
Desde las 12h hasta las 00h
Auditorio La Rodadera, Gerena (Sevilla)
Programa de Terapia Genética (Univ. de Pensilvania)
FAST firma acuerdo con la Universidad de Pensilvania para impulsar estudios preclínicos de terapia génica hasta fase de “nuevo fármaco en investigación” (IND).
17 de octubre de 2023 — La Fundación sin ánimo de lucro FAST (Foundation for Angelman Syndrome Therapeutics) anunció hoy que ha firmado un acuerdo exclusivo de investigación y desarrollo global con la Universidad de Pensilvania para desarrollar un programa de terapia génica basada en virus adenoasociado (AAV) para el síndrome de Angelman (SA).
El síndrome de Angelman es un trastorno neuro-genético no degenerativo que se estima se produce en aproximadamente uno de cada 15.000 nacimientos, o unas 500.000 personas en todo el mundo, y que conlleva importantes necesidades de atención médica no cubiertas, tales como retraso del desarrollo, ausencia de habla, convulsiones, fuerte trastorno del sueño y alteraciones de la motricidad, entre otros síntomas graves. Actualmente ningún país del mundo cuenta con una terapia aprobada para tratar el síndrome de Angelman.
FAST ha financiado estudios de investigación preclínicos en el Programa de Terapia Genética (GTP, por sus siglas en inglés) de la Universidad de Pensilvania (Penn) desde 2017 para desarrollar una terapia génica para el síndrome de Angelman que se administre directamente al sistema nervioso central (SNC). Como ahora se dispone de sólidos datos preclínicos, ya es posible concentrarse en desarrollar un potencial fármaco para uso en humanos a través de la fase de estudios finales de investigación previos a una solicitud de estudios de “nuevo fármaco en investigación” (IND), prerrequisito para realizar posteriormente los primeros ensayos clínicos con pacientes.
Este nuevo acuerdo de colaboración, actualizado y ampliado, permite seguir avanzando a partir de lo obtenido con la financiación inicial que FAST concedió a Penn y permitirá a FAST colaborar más estrechamente con el equipo de Penn para progresar más rápido en lograr que este potencial fármaco llegue a la fase de ensayos clínicos con personas que viven con SA.
«Hemos estado trabajando para decidir si proceder o no desde 2017», dijo Allyson Berent, DVM, DACVIM, Directora Científica de FAST. «Es muy gratificante poder observar los resultados prometedores obtenidos a partir de sólidos datos preclínicos gracias a que FAST no ha cesado de financiar estudios año tras año. En el último año, un gran número de empresas han cambiado sus prioridades en materia de enfermedades raras, pero la prioridad de FAST seguirá inamovible. Nos esforzamos para garantizar que la ciencia basada en la excelencia avance en todo momento de la forma más segura y eficiente posible, y para aprovechar cada oportunidad de poder ayudar a aquellas personas que viven con el síndrome de Angelman».
«Desde el comienzo, nuestra colaboración con el equipo de FAST y la comunidad del síndrome de Angelman ha sido muy productiva y gratificante», comentó el Dr. Jim Wilson, PhD, Director del Programa de Terapia Genética, profesor Rose H. Weiss y director del Centro de Enfermedades Huérfanas y profesor de Medicina y Pediatría en la Facultad de Medicina Perelman de la Universidad de Pensilvania. «Nuestros dos equipos han estado trabajando enfocados en la misión y los datos, colaborando estrechamente para llegar hasta este punto de inflexión clave. FAST y GTP han decidido proceder a continuar desarrollando de forma rápida y segura una prometedora molécula para uso en seres humanos como una potencial terapia genética para tratar el síndrome de Angelman».
ACERCA DE FAST
FAST es la fundación que mayor financiación aporta a la investigación del síndrome de Angelman a nivel mundial. Nuestro objetivo es lograr que tratamientos prácticos se incorporen a la práctica médica de la forma más rápida y segura posible. Tenemos la esperanza de que los programas que financiamos animen a agencias gubernamentales, otras fuentes de financiación y organizaciones de todo el mundo a financiar más proyectos de investigación.
Importante subvención para edición genética (NIH)
Los NIH anuncian una importante subvención para una plataforma de edición genética a la Universidad de Yale, la Fundación para la Terapéutica del Síndrome de Angelman y el Centro Médico Universitario RUSH
3 de octubre de 2023 – Los Institutos Nacionales de la Salud (NIH, por sus siglas en inglés) han concedido este mes la primera fase de una subvención de unos 40 millones de dólares a la Universidad de Yale para impulsar una novedosa plataforma de edición genética basada en CRISPR para el tratamiento dirigido de enfermedades neurogenéticas. Las dos enfermedades objeto del proyecto son el síndrome de Angelman y el síndrome H1-4 (HIST1H1E). El equipo del proyecto nombrado en el marco de la subvención incluye a representantes del equipo del Dr. Yong-Hui Jiang y del Dr. Jiangbing Zhou en Yale, del equipo de la Dra. Elizabeth Berry-Kravis en RUSH, y de la Dra. Allyson Berent y Jennifer Panagoulias de la Fundación para la Terapéutica del Síndrome de Angelman (FAST, por sus siglas en inglés).
La subvención, del NIH Common Fund, forma parte de un programa en dos fases con un presupuesto total propuesto de, aproximadamente, 40 millones de dólares en 5 años. La primera fase, dotada con 26,5 millones de dólares, está dedicada a generar todos los datos preclínicos y otros componentes clave de cara a un ensayo clínico para ambas enfermedades. La segunda fase, de unos 13,4 millones de dólares, está destinada a financiar el ensayo clínico de fase I/II propiamente dicho. La adjudicación de esta segunda fase está supeditada a la finalización con éxito de la primera.
En conjunto, la subvención financia toda la trayectoria de desarrollo del fármaco, desde los estudios de prueba de concepto hasta los estudios del producto en fase de investigación clínica (PEI o IND, por sus siglas en inglés), necesarios para un ensayo clínico, y el ensayo clínico de fase I/II para ambas enfermedades.
La nueva tecnología de administración —denominada plataforma de ingeniería sin trazas y sensible a estímulos (STEP, por sus siglas en inglés)— permite administrar ribonucleoproteínas (RNP) en todo el cerebro por vía intratecal y tiene el potencial de curar enfermedades cerebrales con un único tratamiento. La tecnología fue desarrollada y caracterizada por el equipo dirigido conjuntamente por los doctores Jiang y Zhou.
«Como plataforma tecnológica versátil, las RNP creadas con STEP podrían utilizarse para el tratamiento de muchos trastornos neurogenéticos», declaró el Dr Jiangbing Zhou.
En el caso del síndrome de Angelman, los resultados obtenidos hasta la fecha son muy prometedores en el modelo de ratón, tanto en el nacimiento como en la edad adulta, con una amplia biodistribución cerebral y un efecto duradero. Es importante destacar que la plataforma de edición genética evita la necesidad de la administración viral, que es la forma habitual en que las tecnologías CRISPR se han administrado en el cerebro. El equipo FAST, dirigido por las doctoras Allyson Berent y Jennifer Panagoulias, apoyará los estudios de PEI y la estrategia reguladora necesarios para llevar esta tecnología a los pacientes con SA. Los primeros datos preclínicos sobre el síndrome H1-4 también parecen prometedores.
«En nuestro modelo de ratón del síndrome de Angelman, observamos una edición genética muy eficaz en las neuronas de todo el cerebro, acompañada de la reactivación del gen Ube3a y de mejoras en los fenotipos neuroconductuales», afirmó el Dr Yong-Hui Jiang. «Es asombroso».
Siempre que se alcancen hitos satisfactorios, los ensayos clínicos en humanos de este programa se llevarán a cabo tanto en Yale como en el Centro F.A.S.T. de Investigación Traslacional de Rush, un centro pionero en su género creado el año pasado gracias a una donación de 5 millones de dólares del grupo de defensa de los pacientes. El equipo de FAST de RUSH también trabajará para aumentar el acceso a estos tratamientos, aportando su amplia experiencia en el diseño y la realización de ensayos clínicos.
«Esta es la razón por la que se creó el Centro F.A.S.T de Investigación Traslacional de RUSH: para poder llevar a cabo ensayos clínicos novedosos, innovadores y potencialmente transformadores para el síndrome de Angelman», afirmó la Dra. Elizabeth Berry-Kravis, MD, PhD, profesora de pediatría y ciencias neurológicas y directora del Centro F.A.S.T. de Investigación Traslacional en Neurociencias Pediátricas de Rush de la Universidad RUSH de Chicago. «Este programa encaja a la perfección, ya que nos esforzamos por formar a más médicos en todo el mundo para que comprendan la forma más eficaz de llevar este tipo de tratamientos al mayor número de pacientes».
Esta nueva subvención apoya la traslación de tecnologías prometedoras del laboratorio a la clínica, donde los pacientes se pueden beneficiar directamente —lo que se conoce como «del laboratorio al paciente»—, que es el sello distintivo de la estrategia única de defensa del paciente de FAST. El grupo, el mayor financiador de la investigación sobre el síndrome de Angelman en el mundo, se dedica a introducir un tratamiento eficaz en la práctica médica actual.
Aprende más sobre la escala ORCA
Esta semana destacamos dos nuevas publicaciones financiadas por FAST sobre ORCA (Observer-Reportes Communication Ability), la escala para medir la Capacidad de Comunicación para personas con síndrome de Angelman. La comunicación es esencial para el funcionamiento diario y ha sido identificada por los cuidadores como una de las principales prioridades en la que centrarse para la eficacia del tratamiento en los ensayos clínicos.
Dado que muchas personas con SA no suelen pronunciar palabras verbalmente, sino que tienen muchas otras formas de comunicarse, como gestos, aproximaciones de palabras y el uso de sistemas de símbolos o un sistema de CAA, es difícil conocer su verdadera capacidad de comunicación a través de medidas estandarizadas. Casi todas las medidas existentes no tienen en cuenta todas las formas de comunicación de las personas con SA, y todos sabemos que esto lo aprecian más quienes mejor las conocen, sus cuidadores. Reconociendo esta limitación, la FAST encargó a los doctores Bryce Reeve y Christina Zigler de la Universidad de Duke que diseñaran y validaran una nueva herramienta de comunicación adaptada específicamente a la comunidad de personas con SA, denominada “medida de la capacidad de comunicación informada por el observador” (ORCA, por sus siglas en inglés). Esta medida de resultados, o herramienta diseñada para medir el cambio en un ensayo clínico, fue financiada por el FAST tras recibir algunas orientaciones de personas de la FDA. Los miembros del equipo FAST estuvieron muy implicados en su desarrollo para garantizar que esta herramienta reflejara las capacidades comunicativas de todas las personas con síndrome de Angelman.
ORCA es una escala informada por el cuidador que divide la comunicación en 3 conceptos principales: comunicación expresiva, receptiva y práctica. El equipo de ORCA define la comunicación expresiva como las interacciones en las que la persona con SA comunica algo a su interlocutor, la comunicación receptiva como el proceso de comprensión de un mensaje expresado por un interlocutor y la comunicación pragmática como la comunicación adecuada en entornos sociales. El equipo entrevistó primero a 22 cuidadores de personas con SA de todos los genotipos para comprender los tipos de funciones comunicativas observadas. Dentro de la comunicación expresiva eran comunes funciones como solicitar objetos, lugares o entretenimiento. Las personas con SA también podían llamar la atención de los cuidadores, pedir más de algo y rechazar objetos. Los cuidadores informaron que los individuos con SA podían hacer comentarios, definidos como observaciones que expresan opiniones o reacciones, con conductas sencillas como reír o sonreír para expresar felicidad o excitación y vocalizaciones graves cuando estaban descontentos. Dentro de la categoría de comunicación receptiva se observaron funciones como responder a nombres, preguntas de sí/no e instrucciones. Además, los individuos con SA eran capaces de hacer elecciones como elegir una preferencia de comida y comprender palabras aisladas indicadas por la respuesta a nombres familiares y comida. Por último, en cuanto a la comunicación pragmática, los individuos con SA presentaban puntos fuertes como los saludos, la comodidad y el reconocimiento de juegos familiares. Para concluir la entrevista inicial, el equipo de ORCA preguntó qué significaba para cada cuidador un cambio significativo en la comunicación. Las respuestas incluyeron tener una capacidad de comunicación más compleja, iniciar la comunicación y la capacidad de comunicarse más fácilmente con personas ajenas a su familia inmediata.
A partir de este primer estudio de entrevistas a cuidadores, el equipo de Duke redactó una versión preliminar de ORCA y la probó con otros cuidadores. Era importante asegurarse de que esta escala fuera capaz de captar las capacidades de comunicación de todas las personas con SA. Las respuestas a ORCA pasaron a ser “No, sólo una vez”, “A veces” y “Sí, casi siempre” para indicar el desarrollo y el dominio de las habilidades. A partir de estos cambios, el equipo de Duke pudo crear una versión final de la escala ORCA que luego probaron en 249 familias de niños con todos los genotipos de edades comprendidas entre los 2 y los 39 años. A partir de los datos recogidos en este estudio, observaron que ORCA era lo suficientemente sensible como para medir las capacidades de comunicación de SA matizadas en todos los individuos evaluados, y que ningún individuo se salía de la curva de campana, como ocurre en la mayoría de las demás pruebas estandarizadas de capacidades de comunicación. Fue un hallazgo muy interesante. Esta escala se está utilizando ahora en todos los ensayos clínicos activos para el síndrome de Angelman, como primer punto final o medida de resultados desarrollada específicamente para el síndrome de Angelman. Además, desde que se inició este proyecto, la FDA concedió a este mismo equipo de Duke una subvención de más de 2 millones de dólares para continuar desarrollando ORCA para otros 13 trastornos del neurodesarrollo, como el síndrome de Angelman, porque estaba claro que existía una gran laguna en las evaluaciones estandarizadas que se utilizan en los ensayos clínicos para todos los trastornos del neurodesarrollo, y esta es una herramienta realmente prometedora para llenar ese vacío para el síndrome de Angelman y otros muchos.