The CDKL5 Forum is an annual “by-invite-only” event hosted by the Loulou Foundation to report on the progression of the CDKL5 Deficiency Disorder field. IFCR board members, Rick Upp and Amanda Jaksha, and Science Director, Heidi Grabenstatter, attended this event that includes scientists, industry representatives, clinicians, and nonprofit leaders invested specifically in CDKL5 Deficiency Disorder (CDD).
It was clear that the rapid progress occurring in CDD research does not happen unless stakeholders are willing to openly collaborate. This collaboration occurred on multiple fronts. For instance, the Loulou foundation has developed and made available online tools to help scientists collaborate and share methods in a more efficient manner. In addition, mechanisms for international nonprofits to share resources and collaborate were discussed. Pharmaceutical companies also reviewed ways they could work together to standardize clinical outcome measures across different trials for CDD. Likewise, a clinical research network designed to validate the clinical outcome measures was presented in detail and the lead investigator encouraged the participation of multiple sites, international patient advocacy groups, federal agencies, and industry partners as collaborators in responsible data stewardship.
Caregivers of CDD patients also play an enormous role in this process. Personal stories contributed to our working knowledge of what outcome measures matter most to CDD families, such as:
- Sleep dysfunction
- GI dysfunction
Reports on current research and bench science were also presented. Some of the research areas impact CDKL5 but are not CDKL5-specific.
The CDKL5 Forum is an annual “by-invite-only” event hosted by the Loulou Foundation to report on the progression of the CDKL5 Deficiency Disorder field. A month has passed since IFCR leaders returned from the annual “by-invite-only” CDKL5 Forum hosted by the Loulou Foundation. Board members, Rick Upp and Amanda Jaksha, and Science Director, Heidi Grabenstatter, attended the unique event that includes scientists, industry representatives, clinicians, and nonprofit leaders invested specifically in CDKL5 Deficiency Disorder (CDD) as attendees. Stakeholders share the newest findings from their respective fields of expertise.
This included updates from the bench:
- “Molecular, imaging, and electrophysiological biomarkers for CDD” that have been developed in animal models were presented by Michela Fagiolini (Boston Children’s Hospital), Massimiliano Bianchi (Trinity College Dublin), and Timothy Roberts (Children’s Hospital of Philadelphia). These alterations, for example microtubule modifications are indicators of CDKL5 protein change that can be used to determine the efficacy of potential treatments.
- “Organoid culture phenotypes and reversal by small molecules” was presented by Dr. Alysson Moutri (UCSD). This work is an example of new screening method to develop novel compounds specifically targeting mini brains developed in the dish from CDD patient cells.
- “Phosphoproteomics as a tool for identification of downstream CDKL5 phosphorylation targets using CDD iPSC lines and isogenic controls” was presented by Nicole Van Bergen (Murdoch Children’s Research Institute). This work uses patient derived cells to better understand the proteins that CDKL5 talks to in its signaling pathway in an effort to define targets for therapeutics.
- “Update on animal model phenotypes” was presented by Joe Zhou (University of Pennsylvania) demonstrated some evidence that R59X knockin and CDKL5 knockout (exon 6 deletion) mouse lines have spontaneous seizures. Following prolonged monitoring, the R59X knockin heterozygous female and CDKL5 knockout heterozygous female mice had severe seizures without additional perturbation. These results begin to demonstrate the construct validity of two CDD mouse models for the epilepsy phenotype that is known to be clinically prevalent in CDD. These results emphasize that the time-dependent development of seizures is reproducible across different CDD mouse strains.
- “Sleep phenotyping in the CDKL5 knockout mouse model” was presented by Liqin Cao (University of Tsukuba, Japan). This research demonstrates altered sleep architecture in cdkl5 knockout mouse, specifically less REM sleep, frequent awakening, low sleep efficiency, and daytime somnolence in CDD mice.
- “Pre-clinical studies demonstrating an effect of CBD on evoked seizures and behavioral abnormalities in R59X mice” were presented by Francis Jensen (University of Pennsylvania). These studies demonstrated an effective of CBD on behavioral deficits and evoked seizures in the r59x mouse model of CDD.
- “Pregnenolone-methyl ether targets CLIP-170 and restores hippocampal-dependent learning and memory deficits and synaptic deficits in vivo in CDKL5 KO mouse” presented by Charlotte Kilstrup-Nielsen (University of Insubria). Microtubule associated proteins (found in dendrites) and CLIP-170 (a protein found in the axons of neurons) are overexpressed in CDD. Prenenolone Methyl Ether (PME) is a potential therapeutic that restores levels in vivo and in vitro, but also corrects behavior defects, and dendritic spine defects. More on this work can be found in a new publication found here.
- “New phosphodiesterase (PDE) 10A inhibitor from Takeda that received orphan drug designation also impacts motor functions and behavioral phenotypes in animal models of CDD.” -presented by Christine Charman (Takeda Pharmaceutical). This is early proof-of-principle work conducted by industry to move an orphan drug down the pipeline to patients.
- “X chromosome inactivation by DNA methylation editing of the CDKL5 gene promotor” was presented by Kyle Fink (UC Davis) In cell lines, dead Cas 9/CRISPR is used to reactivate the good copy of CDKL5 in the “inactive” X chromosome. This is early work demonstrating a potential therapeutic pathway for girls with CDD.
- Jim Wilson from University of Pennsylvania presents correction of CDD behavioral phenotypes using gene therapy in neonatal CDKL5 knockout mice. These studies demonstrate the feasibility of viral vector use for CDKL5 delivery to reverse CDD symptoms in this time window.
Presentations from companies including:
- Overview of gene therapy strategies and associated challenges including viral delivery:
- Amicus developing enzyme replacement therapy
- Ultragenyx developing gene therapy
- Invitae presented a no-charge genetic testing program for pediatric epilepsy and what they have learned so far.
- Marinus updated attendees on their progress in the Phase 3 Marigold trial for Ganaxalone and announced that enrollment is on track and that recruitment will be completed soon. The company expects top-line results in 3Q2020.
Clinical research presentations included:
- Heather Olson, the director of the Boston Children’s Hospital CDKL5 Center of Excellence, presented visual acuity as a quantitative and dynamic translatable outcome measure for CDD.
- Timothy Roberts from Children’s Hospital of Philadelphia shared efforts towards developing electrophysiological biomarkers including the experience of other neurodevelopmental disorders like Rett Syndrome and how it translates to CDD.
- Scott Demarest of Children’s Hospital Colorado and the lead investigator of the International CDKL5 Clinical Research Network, shared the necessary steps and known obstacles to developing validated clinical outcome measures for CDD.
Breakout sessions were held covering a number of pertinent topics to scientists, clinicians, industry leaders, and parents. These included a collection of topics that were chosen to help prepare a “Translational toolbox” aimed to help the collective community have readiness for disease-modifying therapies:
- Genetics, molecular and functional biology of CDD
- In vitro assay development for CDD drug discovery
- In vivo assays and behavioral pharmacology for CDD drug discovery and development
- Translational biomarker discovery and validation for CDD
- Clinical Trial Design and Execution
- Clinical outcomes development for CDD (Epilepsy)
- Clinical outcomes development for CDD (Non-epilepsy)
- Patient partnership in development of therapies for CDD
What is readily apparent is this a multi-tiered “toolbox.” Clinical-trial readiness and clinical translation do not happen at one level, but require multiple stakeholders working together!
This year, a very encouraging theme emerged. As a second-time attendee, I left understanding that the rapid progress that is occurring in CDKL5 Deficiency Disorder does not occur unless stakeholders are willing to openly collaborate. Within the breakout sessions, presentations, and satellite meetings, mechanisms for international nonprofits to share resources and collaborate were discussed, the Loulou foundation has developed and made available online tools to help scientists collaborate and share methods in a more efficient manner, pharmaceutical companies discussed ways they can work together to standardize clinical outcome measures across different trials for CDD. Likewise, a clinical research network designed to validate the clinical outcome measures was presented in detail and the lead investigator encouraged the participation of multiple sites, international patient advocacy groups, federal agencies, and industry partners as collaborators in responsible data stewardship.
The CDD community is doing something else notably well and I attribute this to the active caregiver and clinician community. As caregivers, you worry about your child today and the consequences that CDD has tomorrow and years down the road. We are fortunate to work with visionary investigators and parents that recognize it is not just what we are doing today, but how we anticipate the needs of the field tomorrow that will make us successful (or not). This is one way to propel the CDD field forward at a rapid pace and de-risk the disorder for treatment development. Funders and advocacy groups in the CDD space are especially good at recognizing gaps early, noting the strengths held by different stakeholders, communicating what entity will be responsible for filling a specific gap, and throwing themselves into their respective work with abandon. Our partners at the Loulou foundation have fund basic and translational science at a record pace. Patient advocacy groups have also contributed in this area of research funding. The LouLou foundation also works hard with industry partners to ensure potential treatments for CDD meet regulatory expectations.
Outside experts including NCATS Office of Rare Disease Research Director, Dr. Anne Pariser, were invited to the CDKL5 Forum from regulatory agencies to discuss how clinical trials are developed, what is needed from Natural History Studies and what is required in a validated clinical outcome measure to move treatments forward. This is the work IFCR is working on with our primary focus being establishment of new CDKL5 Centers of Excellence, quality patient care, and support of clinical research.
Amazing scientists that are making breakthroughs in rare disease treatment options including Dr. Timothy Yu of Boston Children’s University and David Liu from the Broad Institute were invited to present their work on an n=1 antisense oligonucleotide (ASO) therapy and prime editing, respectively. ASO therapy utilizes a specific change in the patient that must be amenable to this approach and is often intronic. Targeting with ASOs prevents expression of the mutant allele. An ASO, itself, is a small fragment of DNA that binds allowing a modified protein to function in place of the lost mutant protein. Prime editing is a different approach that corrects single letters (A,T,G, etc) that are responsible for genetic disorders, however, that is only one of many steps on the road to clinical trial. The technology must be vetted in animals and in the organ (i.e., the brain) that is affected. The science is moving fast and the Forum infuses a feeling of hope into the community regarding directions the CDD community may move in the future. IFCR and its CDKL5 Clinical Trial Research Network will make sure the community is armed with validated clinical outcome measures when these therapies are available for clinical trials. The hope of the future, the treatments of tomorrow, can only come to fruition if we prepare now.
On the heels of the PFDD meeting, please know that caregivers of CDD patients play an enormous role in this process. Those of you that shared your story in person or online have contributed to our working knowledge of what outcome measures matter most to CDD families. The “outcome measures” breakout session attended by pharmaceutical companies, nonprofit organization leaders, clinicians, and caregivers produced a working list of outcomes that aligned remarkably well with those that were rated as having the highest impact on caregivers from the PFDD conference:
- Sleep dysfunction
- GI dysfunction
The lines of communication are actively being installed between the necessary players. You have now made your voice heard to the clinicians, the companies, and the FDA! The Patient Voice will continue to be heard and infused into the shared mission of the stakeholders thanks to new tools like Connect CDKL5 built by IFCR which breaks down barriers between all international patient advocacy groups.
Dr. Daniel Lavery, CSO of the Loulou Foundation, did a fine job of organizing a Forum that provided diverse community members with the visibility to showcase the work that had been diligently developing over the course of the previous year. He highlighted both the difficulties inherent to translating basic research to the clinic, but also, the progress that a team can make if they focus efforts on separate puzzle pieces that come together as a shared goal … treatments and cures for CDKL5 Deficiency Disorder.