Chemical Chaperone Therapy for Developmental and Epileptic Encephalopathies (DEEs) – Identifying Candidates Via Literature Review

Abstract number : 1.042
Submission category : 1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year : 2021
Submission ID : 1826368
Source : www.aesnet.org
Presentation date : 12/4/2021 12:00:00 PM
Published date : Nov 22, 2021, 06:53 AM

Authors :
Kerry Gao, BA - Weill Cornell Medical College; Jacqueline Burre, PhD - Assistant Professor, Neuroscience, Weill Cornell Medical College; Scott Demarest, MD - Assistant Professor, Neurology, Children's Hospital Colarado; Zachary Grinspan, MD, MS - Associate Professor, Population Health Sciences, Weill Cornell Medical College

Rationale: Chemical chaperones can help restore function to misfolded proteins and are a promising novel therapy for DEEs. For example, phenylbutyrate (a potential chemical chaperone) improves the function of STXBP1 in animal models and is currently under evaluation in a clinical trial. If successful, this raises the question of whether other DEEs might benefit from this strategy. We conducted a targeted literature review to identify candidate DEEs for additional investigation of this therapeutic strategy.

Methods: Through expert consensus, we generated a list of ad hoc criteria for the potential success of chaperone therapy based on research feasibility and translational applicability. We then performed a literature review to classify 38 epilepsy genes by these criteria (Table 1; The 38 genes were based on which specific genes are tracked in the Pediatric Epilepsy Learning Healthcare System). We then reviewed findings and ranked the genes into tiers (“promising,” “possible,” and “unlikely”) based on expert review by one author (JB). Our five criteria were: mutations cause loss of function (stabilizing gain of function protein potentially exacerbates problem), size less than 90 kD (lentiviral vectors can only accommodate so much cDNA), less than 5 hetero-subunits (avoid the need for stoichiometric assembly), cytosolic localization (ease of purification), and autosomal dominant disease (x-linked reduces viable culture by half; autosomal-recessive requires homozygosity for clinical phenotype).

Results: 5 genes were “promising,” meeting 5/5 criteria: DNM1, FOXG1, GNAO1, STX1B, STXBP1. 12 genes were “possible,” meeting 4/5 criteria: CDH2, UBE3A, SYNGAP1, TSC1, TSC2, DEPDC5, PRRT2, SLC13A5, SLC2A1, SCN2B, MECP2, ALDH7A1. 21 genes were “unlikely,” meeting 3/5 criteria or fewer.

Conclusions: Our review has identified 5 promising candidate DEEs for chemical chaperone research and therapy. The next step is to evaluate whether chemical chaperones can rescue different mutants in laboratory models—keeping in mind in-vitro efficacy may be influenced by target protein isoforms and mutation variants. Identifying suitable genotypes in which chaperone therapy successfully restores protein function would lay the foundation for human clinical trials.

Funding: Please list any funding that was received in support of this abstract.: Morris and Alma Schapiro Fund.

Basic Mechanisms