RNA-targeted Therapy Offers Breakthrough in Aicardi-Goutières Syndrome

Researchers from the University of Sydney have announced a breakthrough in the treatment of Aicardi-Goutières Syndrome (AGS). Published in The Journal of Clinical Investigation, their study introduces a promising RNA-targeted therapy that effectively halts the progression of AGS in mice. The therapy targets the interferon alpha receptor using antisense oligonucleotides, reducing neuroinflammation and neuronal damage while restoring the integrity of the blood-brain barrier. The findings offer hope for potential reversal of AGS's detrimental effects and lay the groundwork for future human trials.

The study represents a significant advancement in AGS research and treatment. Lead author Dr. Barney Viengkhou and Research Director Patrick Winters of the Aicardi-Goutières Syndrome Advocacy Association express enthusiasm for the therapy's potential to alleviate the burden on affected families. Conducted in collaboration with Ionis Pharmaceuticals and Biogen, the research not only promises to transform the lives of children with AGS but also offers hope for therapy development in other childhood dementias, highlighting the urgent need for innovative treatments and support for affected families.

Read the press release from the University of Sydney:
New therapy shows promise for a rare childhood dementia. 18 April 2024

Read the paper from the Journal of Clinical Investigation:
Viengkhou, Barney et al. “Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy.” The Journal of clinical investigation vol. 134,4 e169562. 9 Jan. 2024, doi:10.1172/JCI169562

Muscle Tone Management

Muscle Tone Management

Explanation, Medications, Therapies

Understanding Abnormal Muscle Tone

The first image shows a child with spasticity in the legs, the second image shows a child with dystonia in the arms and hands, and the third shows a child with hypotonia requiring support to hold her head upright.

Abnormal Tone in AGS

AGS causes abnormal tone and movement disorders due to neurological injury. These disorders, including dystonia, spasticity, and hypotonia, affect muscle tone and can impact movement and motor function in children with AGS. As AGS can present differently in each individual, symptoms may vary in severity and affect different muscle groups. Families may benefit from looking to Cerebral Palsy as a model for information about management and treatment.

Spasticity, Dystonia, and Hypotonia

Spasticity

A condition in which there is an abnormal increase in muscle tone or stiffness of muscle, which might interfere with movement, speech, or be associated with discomfort or pain.

Dystonia

A movement disorder characterized by involuntary muscle contractions that cause slow repetitive movements or abnormal postures.

Hypotonia

A term that describes decreased muscle tone. It is not the same as muscle weakness, although the two conditions can happen at the same time.

Managing Muscle Tone in Disabled Children

There are various approaches to managing muscle tone, and we recommend referring to this resource for a comprehensive understanding of their evidence-based effectiveness.

Novak, Iona et al. “State of the Evidence Traffic Lights 2019: Systematic Review of Interventions for Preventing and Treating Children with Cerebral Palsy.” Current neurology and neuroscience reports vol. 20,2 3. 21 Feb. 2020, doi:10.1007/s11910-020-1022-z

Physical Therapy

Physical therapy is a common method used to manage spasticity and dystonia in children. It involves exercises and stretches that help improve muscle control and flexibility.

Botulinum Toxin and Phenol Injections

Botulinum toxin, commonly known as Botox, is a medication that can be injected directly into muscles to temporarily weaken them. Phenol is a chemical that can be used to temporarily deaden nerves in a muscle, which can reduce spasticity. Either of these can help reduce spasticity and improve range of motion. Injections are usually given every few months under sedation and may have side effects such as pain, bruising, and weakness.

Medications

Medications such as Baclofen and Diazepam can be used to reduce spasticity and muscle rigidity. However, they may have side effects such as drowsiness and weakness. Usually taken orally, baclofen can also be delivered by a medical device that is surgically implanted into the abdomen to deliver medication directly into the spinal cord.

Surgeries

As a last resort, surgical interventions may be necessary to release tight muscles and improve mobility. Surgeries are usually considered when other treatments have not been effective. Joint contractures, hip dislocations, scoliosis, and deformed extremities may result from unmanaged spasticity and dystonia.

Conclusion

While managing abnormal muscle tone can be challenging for disabled children and their families, there are various methods available to manage these conditions and improve quality of life. Consult with your doctor to determine the best course of action for your child.

The AGS Scale

What is the AGS Scale?

The AGS Scale is a way for doctors to measure how severe the outcomes are for people with Aicardi Goutières Syndrome (AGS). The team at the Children's Hospital of Philadelphia developed a short, simple questionnaire that scores the severity of a person's overall global neurologic dysfunction. The scale is easy to apply and remains relevant to AGS' unique challenges. It was developed to better understand how individuals affected by AGS change over time.

Why is a neurologic severity scale important for AGS?

Doctors use the AGS Scale to track how Aicardi Goutières Syndrome (AGS) is affecting a patient over time. This helps them determine whether the patient's condition is improving or worsening. This helps doctors make better decisions about how to treat the patient and can help families better understand the course of the disease. The scale also helps researchers study the disease and measure the effect of new treatments.

How was the neurologic severity scale developed?

A team of AGS experts from the U.S. and Italy worked together to create the AGS Scale. They reviewed patient medical records and chose features that could help determine the severity of the disease, including motor, cognitive, and communication abilities. To make sure the results were consistent, multiple doctors examined many patient records and applied the AGS Scale. They then compared the scores from the AGS Scale with results from other scales to ensure that the results were meaningful.

How do I apply the scale?

For each item in a list, a patient can receive one point, and the maximum score is 11.

• Normocephaly (absence of microcephaly)

• Social Smile

• Vocalizations (cooing or babbling)

• Single, meaningful words

• Minimum of three-word phrases

• Head Control (>60 seconds)

• Pincer grasp or self-feeding

• Independent Sitting (>2 minutes)

• Rolling or crawling to goal

• Ambulation with assistance (devices or two-hand assist)

• Independent Ambulation

How do scores compare?

Scores can be compared by AGS type (or gene) and with how doctors considered patients to have "mild", "moderate", or "severe" AGS.

Adang, Laura A et al. “Development of a neurologic severity scale for Aicardi Goutières Syndrome.” Molecular genetics and metabolism vol. 130,2 (2020): 153-160. doi:10.1016/j.ymgme.2020.03.008

How do scores change over time?

For most patients studied, the AGS Scale scores changed the most in the first six months after they were diagnosed with AGS. After that, the scores generally stayed the same. While this stability can be seen as a good thing, it can also mean that patients are less likely to develop new abilities over time. However, in a clinical trial for baricitinib, most children treated with JAK inhibitors saw improving scores on the AGS Scale. This shows that the treatment had a positive effect on their symptoms, and the AGS Scale was important in demonstrating this effect.

AGS Scale & JAK Inhibition

The AGS scale demonstrated that baricitinib (a JAK inhibitor) helped patients with AGS gain new abilities and reach new milestones. For more information, visit agsaa.org/jaki

Vanderver, Adeline et al. “Janus Kinase Inhibition in the Aicardi-Goutières Syndrome.” The New England journal of medicine vol. 383,10 (2020): 986-989. doi:10.1056/NEJMc2001362

What are the AGS Scale's limitations?

While the AGS Scale is helpful in measuring how a person's abilities change over time, it only looks at their abilities in broad terms. People with AGS have a wide range of abilities and intelligence, and this scale cannot fully capture all of their potential. We should not let the AGS Scale limit the opportunities available to people with AGS. Instead, we should focus on helping them to develop their strengths and abilities to the fullest extent possible.

Late-Onset AGS

A description of "late-onset" AGS based on 34 children whose disease presented after a year of age.

Late-onset AGS Appears to be More variable

Children with late-onset (aka "atypical") AGS can be different from each other. The clinical course, brain injury, and developmental outcomes of children with late-onset AGS fall on a wider spectrum than that of early infantile onset.

Diagnostic Failures in Atypical AGS Are Common

Diagnosis is complicated by the fact that late-onset children often do not have classical AGS MRI findings (e.g. few have calcifications). While the majority have a medical encounter within a few days of onset, the median time to brain imaging (MRI) is over a month. And, many take over a year to be properly diagnosed. Misdiagnosis is common.

Late-Onset Children Suffer Complications Before Disease Onset

The majority of children with late-onset AGS have a history of AGS-related complications prior to the severe onset of disease. Chilblains, systemic inflammation, irritability, developmental delay and aseptic fevers are common.

Symptoms Worsen Just before AGS HITS

After the early phase, most individuals with atypical AGS demonstrate increasing and worsening features of systemic inflammation during what is called a “prodromal” period. This period typically starts around 1 year and 3 months of age and often includes developmental delay, fevers, irritability, etc.

Then They Crash

AGS causes more severe neurological injury during what is called the "fulminant" phase. This period typically starts about one month after the "prodromal" period and can result in the development of spasticity and dystonia and the loss of gross motor function, vocabulary, and speech.

And Wait For Relief

The length of the "fulminant" phase can vary greatly, but about half of children will have experienced the worst of it within 4 weeks. For a few it fade within one week; while for many others (over one-third) it may continue longer and be considered "chronic."

Piccoli, Cara et al. “Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features.” Pediatric neurology vol. 115 (2021): 1-6. doi:10.1016/j.pediatrneurol.2020.10.012

SARS-CoV-2 mRNA-based vaccines in the Aicardi Goutières Syndrome

Participants of the AGS Patient Registry contributed directly to this recent publication in Molecular Genetics and Metabolism finding COVID-19 vaccination to be generally safe in the AGS population. Two big 👏 👏 for everyone in the AGS community that contributed their experiences.

"These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated." https://doi.org/10.1016/j.ymgme.2022.10.001

Accelerating Research Through Patient Advocacy

Over the past couple of weeks, we’ve been making the rounds to deepen our connections with scientists and researchers working directly and indirectly on AGS. Our Rare Researcher Grant has provided us with a starting point for many of these conversations, and we’re grateful to the AGS community for demonstrating their grit to our new collaborators. Many would like to share some of their work with our community, and we’re discussing options like webinars and conferences.

Dr. Markus Hofer from the University of Sydney presenting preliminary findings to Devon Cordova and Patrick Winters from a draft manuscript of his most recent work.

Unsurprisingly, we’ve found that our community has some major opportunities and a big role to play in forging projects and framing context for scientists that don’t currently have a personal relationship with Aicardi-Goutieres Syndrome. Many would like to better understand the impact their work could have on real people, and we’ve even been asked to organize meet and greets for students. The work that these laboratories accomplish requires a deep focus on micro and macro biology that can be difficult to relate to stories and experience like we’ve been sharing on social media (@agsamericas). Furthermore, the narrow focus required by their work means that many labs would benefit from the AGSAA sharing broader and more up-to-date insights about our disorder and it’s human impact. Additionally, many would benefit from our guidance and support, opening the door to additional funding opportunities. As proof, the AGSAA will be partnering with Dr. Alysson Muotri to apply for a $2 million dollar “Patient Partnered Collaborations” grant offered by the Chan Zuckerberg Initiative and writing a letter of support to bolster a grant application by Dr. Miroslaw Janowski for his work to better deliver, measure, and characterize therapeutic agents delivered to the CNS.

Developing Therapies and the Importance of Patient and Family Reported Outcomes

This week we’ve come to an agreement with Dr. Joanne Kurtzberg (director of the Marcus Center for Cellular Cures and long time advocate for leukodystrophies) to begin planning and designing a trial to expand a potential cellular therapy for AGS. Some in our community may already be aware that one of Dr. Kurtzberg’s AGS patients has been the subject of a single patient Investigational New Drug (IND) for the use of cord blood derived Mesenchymal Stromal Cells as a downstream, anti-inflammatory therapy. Measuring biomarker and clinical improvements has been difficult in AGS, but the parent and provider reported experiences within this IND have been encouraging enough to pursue it further. The AGSAA will work with Dr. Kurtzberg and others this year to explore yet another opportunity!

In rare diseases, parents, families, and community members often have to take the initiative to explore opportunities for developing therapies. Sometimes we find ourselves in the right place at the right time, but the complexities of developing treatments and clinical trials can be daunting. In addition to deep fundraising, we’re often involved in the trial design and recruitment processes. The community’s input is critical to developing relevant outcomes and measures that could lead to a successful trial. As we explore new therapeutic options in Aicardi-Goutieres Syndrome, we keep returning to these difficulties. We at the AGSAA expect to be working closely this year with academia, industry, and our community to design the best possible clinical trials with the highest chance of success; and we need our families in the AGS Patient Registry to make it happen.

Industry Partners, Promising Developments!

On Friday, Terry Fang, Director of the Genetic and Neurodevelopmental Disorders group at Biogen, gave the AGSAA an update on work they have done over the last few years to bring a potential new therapy to Aicardi-Goutieres Syndrome. The AGSAA’s research committee (Megan Veuleman, Juan Fran Navarro, Patrick Winters, and Devon Cordova) listened intently to some really compelling data and evidence. We’re all in agreement to bring this update to the community soon in the form of a webinar, and we’ll work to include an explanation from Biogen of why participation in the AGS Patient Registry will be critical to developing a successful clinical trial.