Multi-site validation of biomarkers and core clinical outcome measures for clinical trial readiness in CDKL5 Deficiency Disorder - Supplement

Project Summary/Abstract - [From parent grant U01NS114312]
Pathogenic variants in the Cyclin-dependent kinase like 5 (CDKL5) gene cause CDKL5 deficiency disorder
(CDD, MIM 300672, 105830) a severe developmental and epileptic encephalopathy (DEE) associated with
cognitive and motor dysfunction and cortical visual impairment. Recent data suggest CDD is one of the most
common genetic causes of DEE. Work in CDD animal models has demonstrated the ability for disease
modification and symptom reversal: worldwide efforts are now underway to develop therapeutic strategies
(including gene therapy) to treat and potentially cure CDD. While there are four active clinical trials, none
assesses the full spectrum of this DEE to address true disease modification. While capability for disease
modifying therapies is accelerating, there is a critical barrier for clinical trial readiness that may result
in failure of these therapies, not due to lack of efficacy but due to lack of validated outcome measures.
CDD has been associated historically with Rett syndrome but there are many clear distinctions and CDD
has emerged as an independent disorder. Some Clinical Outcome Measures (COMs) can be adapted from Rett
syndrome COMs, whereas others need to be developed specifically for CDD. Our research network is uniquely
positioned to develop clinical trial readiness for CDD by pairing exceptional experience in the development and
validation of outcome measures with an extensive network of CDD experts and clinical trialists. Our goals are
to 1) refine and validate appropriate quantitative COMs and biomarkers and 2) conduct a multi-site clinical trial
readiness study to ensure that they can be successfully implemented. We will test the hypothesis that CDD
specific COMs can be refined to accurately and reproducibly track meaningful changes in clinical trials:
Aim 1: Generate and validate a suite of COMs and biomarkers necessary to comprehensively assess
disease modification in CDD.
Aim 2: Conduct a multi-site clinical trial readiness study to assess implementation, longitudinal stability,
and collect baseline COMs and EEG/evoked potential data.
Overall Impact: These outcome measures will establish clinical trial readiness for CDD and generate historic
baseline outcome data, ensuring optimal testing of potential new therapeutics including gene therapy.
Furthermore, these measures will be adaptable to other DEEs by enabling choices of outcome measures beyond
existing NINDS supported measurement tools (NeuroQoL, PROMIS, Toolbox) that are not designed for the
severity of the DEE populations.

Grant Number: 3U01NS114312-05S1
NIH Institute/Center: NIH
Principal Investigator: TIMOTHY BENKE