Vol. XXV - October 2024 | Email Us | CDGCARE.org

In this Issue

• CDG CARE Receives CZI Award
• Bella Angel Memorial Program Launch
• NGLY1-CDDG Clinical Trial Opportunity
• Epalrestat Clinical Trial Update & Next Steps
• FCDGC Research Publications
• Advocacy Corner & 2024 Annual Giving Tuesday Campaign

CDG CARE Awarded $800,000 Grant from the Chan Zuckerberg Initiative Rare As One Project

CDG CARE is thrilled to announce that we have been selected as one of 31 rare disease patient organizations worldwide to receive a prestigious five-year, $800,000 grant from the Chan Zuckerberg Initiative (CZI) Rare As One Cycle 3 grant program. This significant support will enable CDG CARE to enhance our capacity as a patient-led organization, accelerating research, fostering collaboration, and amplifying the voices of our community.

Advancing Research Through Patient Power

At the heart of the CZI Rare As One Project is the belief that patients, alongside researchers, clinicians, and advocacy organizations, play a pivotal role in driving progress against rare diseases. The Rare As One initiative empowers patient communities to take a leadership role in shaping the research agenda, creating a model where collaboration is key to advancing cures and treatments.

Through this transformative grant, CDG CARE will work to build a robust, collaborative research network focused on inborn errors of metabolism (IEMs), one of the core disease classes supported by CZI. This network will bring together patients, clinicians, and basic researchers to establish shared research priorities, foster innovation, and ultimately accelerate breakthroughs in the field of Congenital Disorders of Glycosylation (CDG).

Joining a Global Cohort of Rare Disease Advocates

As part of the Rare As One Network, CDG CARE joins a cohort of patient-led organizations focused on three scientific areas: channelopathies, ciliopathies, and inborn errors of metabolism. Over the next five years, CZI will provide awardees with resources to strengthen organizational capacity, host community convenings, and develop patient-prioritized research agendas.

By actively participating in this global network, CDG CARE will not only deepen its impact within the CDG community but also collaborate with other rare disease organizations to develop research proposals and address shared challenges. The end goal is to ensure that research is patient-driven and that scientific advancements are aligned with the needs and priorities of those most affected.

A Future Fueled by Collaboration

This grant is more than just financial support; it’s a commitment to building lasting partnerships and creating an environment where patients, researchers, and clinicians can work together toward a common goal. With CZI’s guidance, CDG CARE will continue to grow, learn, and push the boundaries of what is possible in rare disease research.

As we embark on this journey, we extend our deepest gratitude to the Chan Zuckerberg Initiative for believing in the power of patients and for investing in a future where rare diseases, like CDG, can be better understood and treated. Together, we can drive meaningful change and improve the lives of individuals and families affected by these complex conditions.

To learn more about the Rare As One Network and grantees of this Cycle, Click Here.

CDG CARE Launches the

Bella Angel Memorial Program

CDG CARE is proud to announce the launch of the Bella Angel Memorial Program, a heartfelt initiative designed to honor the memory of CDG angels while offering ongoing support to their families. The program serves as a way to celebrate the lives of those we have lost to NGLY1 and CDG, remembering their strength, resilience, and the profound love they brought into the world.

Honoring Our Angels, Advancing CDG Research

Through CDG CARE's extensive collaboration with medical professionals worldwide, the Bella Angel Memorial Program will not only be a tribute to our CDG angels, but also a platform for learning and research. By studying the experiences of angel families, we hope to gain deeper insights into the challenges they have faced, paving the way for improvements in support services, resources, and clinical outcomes.

This initiative aims to honor our angels by working towards a better future for the entire CDG community. By learning from the experiences of families who have lost loved ones, we hope to drive meaningful changes that will make a difference in the lives of those still affected by CDG.

A Special Dedication: Isabella “Bella” Conneran

The program is named in loving memory of Isabella “Bella” Conneran, whose short but impactful life has already advanced our understanding of CDG. Bella’s legacy will continue to inspire us as we work to support families, improve medical care, and honor all CDG angels. Her story, along with those of other angel families, will help us create lasting improvements in the CDG landscape.

A Note from the Conneran Family

As bereaved parents, nothing brings us more joy than knowing the lasting impact Bella has had on others and will continue to have. That is why, in celebration of her 10th birthday today, October 4th, we are excited to announce the launch of the Bella Angel Memorial Program in partnership with CDG CARE. This program will provide support to bereaved CDG families worldwide, honoring their loved ones in meaningful ways.

We believe: “A life that touches others goes on forever.”

Happy Heavenly Birthday to our Beautiful Bella! We love you and miss you.

Join Us in Honoring Our Angels

The Bella Angel Memorial Program is not just about remembrance—it's about creating a future where CDG families have more support, better resources, and improved clinical outcomes. By enrolling in the program, you can help us honor our CDG angels and ensure that their legacies live on, bringing hope to families around the world.

We invite our angel families to Click Here to join our efforts to honor and learn from our CDG angels. 

Together, we can make a difference. Let's continue to celebrate the lives of those we have lost and work toward a brighter future for all those affected by CDG.

Announcement: New Clinical Trial using GlcNAc in NGLY1-CDDG

The FCDGC is launching a clinical trial testing the effect of the GlcNAc sugar supplement on tear production in individuals with a diagnosis of NGLY1-CDDG. Enrollment is expected to open before the end of 2024. Study participation will last approximately 12 weeks.

The trial will be performed at Seattle Children’s Hospital (Dr. Christina Lam), and Children’s Hospital of Philadelphia (Dr. Andrew Edmondson). More information can be found by Clicking Here.

Families of NGLY1-CDDG patients who are interested can contact the individual study sites to register interest and prepare for enrollment.

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Philadelphia

Investigator: Andrew Edmondson, MD, PhD

Contact: Medhi Youbi, MD, MS

Phone Number: 267-425-1787

Email: youbim@chop.edu

Seattle, Washington, United States, 98105

Seattle Children's Hospital

Investigator: Christina Lam, MD

Contacts: Hayden Vreugdenhil, BS and Seishu Horikoshi, MBA

Phone Numbers: 206-884-1264 and 206-987-7701

Emails: Hayden.Vreugdenhil@SeattleChildrens.org and

Seishu.Horikoshi@seattlechildrens.org

Maggie’s Pearl update to the

PMM2-CDG community:

As CEO of Maggie’s Pearl and on behalf of my team and the clinical team at the Mayo Clinic, I’m thankful to CDG CARE for giving us this space to explain to study participants in the epalrestat Phase 3 trial, and the wider PMM2-CDG community, how we got to this point and what comes next. As many of you have already heard, the epalrestat Phase 3 clinical trial has been closed.

In short, all is not lost. We have learned so much that will increase the likelihood of success of clinical trials in the future. We wouldn’t even be standing here without the sacrifices of families who volunteer in clinical trials, and for that I’m eternally grateful to everyone who participated, despite delays and unexpected extensions. Thank you for your service, it is a true gift to humanity. And I feel the frustration of those families who were randomly assigned to the placebo group but didn’t get a chance to try epalrestat or were only on it for a short time.

This cure odyssey began in January 2020, when Maggie Carmichael became the first person living with PMM2-CDG in the world to try epalrestat in what’s called a single-patient Investigational New Drug (IND) study. The improvements that Maggie experienced inspired another PMM2-CDG parent, Konstantin Feinberg, to initiate a second observational study of epalrestat with his son Ethan. Encouraged by the findings of those “n-of-1” studies, Maggie’s Pearl was cofounded by Perlara and the Carmichael family to develop epalrestat as the first therapy for PMM2-CDG. However, we knew full well that other medicines, including targeted therapies, would still need to be developed to get us a real cure for all PMM2-CDG patients one day.

We all wish that the epalrestat trial – itself a historic achievement as the first randomized, double-blind, placebo-controlled Phase 3 trial for PMM2-CDG – would have reached a different conclusion. However, a review of the data in early August showed that it would not be possible to observe a statistically significant difference in the prespecified clinical trial outcome measures between the placebo treatment group and the epalrestat treatment group. When this happens, as it does in most clinical trials, the study is ended.

So, what comes next? Over the past month, Maggie’s Pearl has been conducting a top-to-bottom evaluation of all the Phase 3 trial data. This comprehensive data review includes what’s called a subgroup analysis, where we examine each study participant’s data on a case-by-case basis. This subgroup analysis allows us to distinguish which study participants are responders, i.e., kids who showed benefit on epalrestat, versus non-responders, i.e., kids who did not show benefit on epalrestat. Maggie’s Pearl is convening the clinical trial team to an in-person meeting at the end of October to review the entirety of the data package and formulate a consensus on publishing all the results.

In the beginning of November, we intend to make the case to FDA that Maggie’s Pearl be allowed to start a new open-label study – meaning no placebo, no randomization, no blinding – that invites families back onto epalrestat if they believe their child was benefiting while on epalrestat during the Phase 3 trial. This new study would allow us to explore better and more sensitive clinical trial outcome measures. For example, we already have what may be a superior biomarker to sorbitol, which proved to be a bust in practice. If FDA agrees with our plan, which will include appropriate safety precautions, we anticipate working with Dr Morava-Kozicz at Mt. Sinai, as well as other clinicians, and being able to enroll participants by the end of the year.

Maggie’s Pearl will host at least one virtual town hall meeting in the second half of October to answer questions from the community. If you’re interested in joining, please email me – ethan@maggiespearl.co – and I will follow up with options.

This story is not over yet, and we have more work to do. Maggie’s Pearl is committed for the long haul. The foundational work that we and so many others have done over the last five years will bear fruit in the form of new medicines. I truly believe that it’s just a matter of time. Onward!

Ethan Perlstein, Ph.D.

CEO of Maggie’s Pearl

AAV9-based PMM2 gene replacement augments PMM2 expression and improves glycosylation in primary fibroblasts of patients with PMM2-CDG

Dr. Kent Lai’s lab at the University of Utah conducted a proof-of-concept study showing that AAV9-PMM2 infection of patient fibroblasts increased PMM2 expression and improved glycosylation.

These findings demonstrate that an AAV9-PMM2 gene replacement therapy could be a promising therapeutic option for those affected by PMM2-CDG.

Click Here to read the full article. 

M. Zhong, B. Balakrishnan, A.J. Guo, and K. Lai

FCDGC, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort

Congenital disorders of glycosylation (CDG) are a large group of rare, inherited disorders that affect a complex process in the body called glycosylation. Because the many different types of CDG are rare and vary widely, not much is known about the progression of this group of disorders.

In this study, researchers are exploring the natural history of CDG. The team is gathering data from 280 individuals with CDG across 9 clinical sites. Now at year 5 of the study, the team is sharing an overview of participant characteristics.

Initial findings include insights on liver function, patient-reported outcomes, and neurological features, as well as information on ultra-rare genetic causes of CDG. Authors note that this study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness.

Click Here to read the full article. Mol Genet Metab. 2024 Aug;142(4):108509. doi: 10.1016/j.ymgme.2024.108509. Epub 2024 Jun 6. PMID: 38959600; PMCID: PMC11299528.

_{Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E. Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort. Mol Genet Metab. 2024 Jun 6;142(4):108509. doi: 10.1016/j.ymgme.2024.108509. Epub ahead of print. PMID: 38959600.}

Coagulation abnormalities and vascular complications are common in PGM1-CDG

PGM1-CDG is a rare genetic disorder. The most common clinical presentations include muscle involvement, cleft palate, growth delay and cardiac involvement. Coagulation abnormalities are among the most common laboratory abnormalities. Many symptoms of PGM1-CDG are treatable with D-galactose (milk-sugar) supplementation.

Here, we aimed to describe the incidence of coagulation abnormalities in PGM1-CDG and their evolution, and the ability of D-gal treatment to improve them in 73 reported individuals. About 70 % of PGM1-CDG individuals were reported to have abnormalities. The most frequently observed abnormality was severe antithrombin deficiency. Four of these individuals had major thrombotic events. Galactose improved antithrombin levels showing its benefit in treating coagulation abnormalities in PGM1-CDG.

We recommend that coagulation parameters should be routinely checked in individuals with PGM1-CDG.

Click Here to read the full article. Mol Genet Metab. 2024 Aug;142(4):108530. doi:10.1016/j.ymgme.2024.108530. Epub 2024 Jul 2. PMID: 38968673.

Radenkovic S, Bleukx S, Engelhardt N, Eklund E, Mercimek-Andrews S, Edmondson AC, Morava E. 

So, you wanna be an advocate?!

Hello! My name is Kara, and I am mom to 5-year-old Blaise, who has PMM2-CDG. He was diagnosed just before his first birthday, and shortly after that time, I joined the CDG CARE Board of Directors and found my way to rare disease advocacy. It is something I have grown very passionate about, and now even do as my day job. I have spoken with several CDG families who are interested in advocacy, but aren’t sure where to start or what to do. I took that as a sign that it is probably worth reaching out to our broader network and see if there are more families who are interested in learning more about advocacy. Whether you have 5 minutes or 5 hours to spend, trust me, you can use your voice for good, and be a force in changing the landscape for our kiddos. 

I am writing because I would like to start a more formal CDG CARE Advocacy group, where we can learn about various initiatives that exist in the rare disease advocacy space, and how you can get involved.

If you are interested in learning more about how you can be a part of a larger voice to change lives- please send me an email at kkberasi@gmail.com. I would love to have more CDG families represented in the advocacy space. There is no reason for any of us to feel alone in this fight, and I hope we can turn the frustration and anger we all feel into fuel for change.