A Partnership to Make New Medicines: MaRS Innovation Launches New Drug Discovery Program Based on UHN Discovery

MaRS Innovation is partnering with Dr. James Eubanks at the University Health Network (UHN) to develop a new treatment for Rett syndrome, a rare developmental disorder found almost exclusively in girls and women.

Infants with Rett syndrome develop and grow normally until the age of 8 to 12 months when symptoms begin appearing. Although the symptoms vary in type and severity, most of the girls and women with the disorder cannot speak or use their hands purposefully. Many also experience seizures that are difficult to control with medications. Presently, there is no cure for Rett syndrome, and the available treatments can only help alleviate symptoms.

Researchers have known for many years that most cases of Rett syndrome are caused by mutations in the MECP2 gene; however, the mechanisms that link these genetic changes to the syndrome’s diverse symptoms are not well understood.

“We believe that we have discovered an important piece of the puzzle,” says Dr. Eubanks, a Senior Scientist at the Krembil Research Institute (UHN) who has been studying the disorder for over 20 years.

MaRS Innovation will initially invest up to $400,000 to help translate Dr. Eubanks’ discovery into a new treatment for Rett syndrome. The funds will support the creation and evaluation of drug-like compounds that target TRPM2, dampening its activity, in the brain of Rett patients. Dr. Mark Reed, a medicinal chemist and head of Krembil’s Centre for Medicinal Chemistry and Drug Discovery, will oversee the work, which will be split between the Centre and the Charles River Discovery site in the United Kingdom. The new partnership will also give Drs. Eubanks and Reed access to MaRS Innovation commercialization services to support further development of any promising treatments.

Large Epilepsy Genetics Study Compares Severe and Less-severe Epilepsies in 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry.

The research team focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE).

The team observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; they saw the strongest enrichment in individuals with severe developmental and epileptic encephalopathies and the least strong in individuals with non-acquired focal epilepsy. Moreover, the research team found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G,EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, andGABRG2 for NAFE.

The research team’s study, the largest epilepsy whole-exome sequencing study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Study Examines Most Common Type of Seizures Found in CDKL5 Deficiency Disorder

OBJECTIVE: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). This study sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones.

METHODS: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit.

RESULTS: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia.

SIGNIFICANCE: The most common seizure types in CDKL5 deficiency disorder (CDD) are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. Cortical visual impairment is a common feature in CDD and is correlated with achieving fewer milestones.

First Known Case of Double Somatic Mosaicism Reported in Girl with Dravet Syndrome

A genetic phenomenon called double somatic mosaicism was found for a first time in a girl with Dravet syndrome, a case study reports.

The study, “Double somatic mosaicism in a child with Dravet syndrome,” was published in Neurology Genetics.

Dravet syndrome, a severe type of epilepsy usually evident during the first year of life, is in about 80% of cases tied to known mutations in the SCN1A gene, which encodes for a sub-unit of a sodium channel called NaV1.1 that is involved in the transmission of electrical signals in the brain.

In about 20% of Dravet patients, however, the disorder’s cause  is unclear. In these cases, it has been proposed that genetic alterations taking place in very early fetal development, and not inherited from the parents, may be the underlying reason.

Investigators at the University of Washington examined whether somatic mosaicism — a phenomenon in which an individual has cells that are genetically different due to a mutation taking place during very early fetal development (shortly after the embryo formed) — could be the reason why some people develop idiopathic (unknown cause) Dravet syndrome.

They used a highly sensitive technique known as deep sequencing to analyze SCN1Aand seven other genes previously linked with the disease (SCN2A, SCN8A, HCN1, GABRA1, GABRG2, STXBP1, and PCDH19) using DNA they isolated from blood or saliva of 20 patients with this type of Dravet syndrome.

“We detected double mosaicism in SCN1A in a patient with Dravet syndrome. Comprehensive studies of disease-relevant tissue will be required to gain a more accurate picture of somatic mosaicism levels and how this affects disease severity,” the scientists concluded.

Epilepsy Research Findings: July 2019

This month’s edition of epilepsy news features recent research suggesting that inducing a seizure prior to surgery is just as effective for pinpointing the brain region where seizures originate as a spontaneous seizure as a spontaneous seizure. In addition, CURE Post-Traumatic Epilepsy initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel published work indicating that the amount of a certain type of cell may increase in the brain following repeated, mild TBIs, causing epilepsy.

Safety updates on several anti-epileptic drugs were reported, including results showing pregabalin may be associated with increased suicidal behavior and other hazards, and that certain drugs used to treat epilepsy may increase the risk of dementia. Studies also highlight the need for improved counseling for safe and effective contraception for women with epilepsy, and the need for resources for people with epilepsy in low-income countries.

Summaries of all highlighted studies follow below. We have organized the findings into Research and Discoveries and Also Notable.

Research and Discoveries

Inducing Seizures to Stop Seizures
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Causing seizures by stimulating the brain may be a convenient and more cost-effective way to determine the brain region where seizures are originating prior to surgery.

New Research Could Help Predict Seizures Before They Happen
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A new study has found a pattern of molecules that appears in the blood before a seizure happens, which may lead to the development of an early warning system.

Pregabalin Associated with Increased Suicidal Behavior and Other Hazards 
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Gabapentinoids, a class of drugs used to treat epilepsy and other neurological disorders, are associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Study Furthers Understanding of the Development of Epilepsy Following Mild Traumatic Brain Injury (TBI)
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Featuring the work of CURE PTE Initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel

A type of cell in the brain called an “atypical astrocyte” may increase following trauma, causing epilepsy following repeated, mild TBIs, according to a study by Drs. Oleskii Shandra and Stefanie Robel.

Even People with Well-Controlled Epilepsy May Be at Risk for Sudden Death
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Featuring the work of former CURE Grantee Elizabeth Donner

A new study shows the risk of Sudden Unexpected Death in Epilepsy (SUDEP) may apply to individuals whose epilepsy is well-controlled. Previous, smaller studies showed that SUDEP risk was highest among those with severe, difficult-to-treat epilepsy, however, this study suggests a sizeable minority of SUDEP occurred in patients thought to be treatment-responsive or to have benign epilepsies. The study found that SUDEP occurred in people who had not taken their last dose of epilepsy medication, those who were sleep deprived, and those who had not had a seizure in at least a year.

Anticholinergic Drugs May Increase Risk of Dementia 
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A study suggests that the possible link between anticholinergic drugs and an increased risk of dementia is strongest for certain classes of anticholinergic drugs, including antiepileptic drugs such as oxcarbazepine and carbamazepine.

Research into Cannabis Dosage Shows Reduced Seizures in Children with Severe Epilepsy
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Medicinal cannabis oil containing both cannabidiol (CBD) and a small amount of tetrahydrocannabinol (THC) can reduce or end seizures in children with severe, drug-resistant epilepsy, a study by the University of Saskatchewan has found.

Also Notable

The World Health Organization (WHO) Highlights the Scarcity of Treatment for Epilepsy in Low-Income Countries
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Three quarters of people living with epilepsy in low-income countries do not get the treatment they need, increasing their risk of dying prematurely and condemning many to a life of stigma, according to WHO.

Bringing Neuromodulation Therapies to Drug-Resistant Epilepsy Patients
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Researchers at the University of Alabama at Birmingham found that creating an epilepsy neuromodulation clinic improved access for patients and communication with referring physicians, achievement of expected outcomes for reducing or eliminating seizures, and the ability to train future providers in programming neuromodulation devices.

Encoded Therapeutics Gets $104M to Propel ‘Precision Gene Therapy’ for Dravet Syndrome
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Encoded Therapeutics received $104 million to fund a precision gene therapy for Dravet syndrome. The company will also use the funds to advance its preclinical programs and come up with new treatments for severe genetic disorders.

Improved Counseling Needed for Safe, Effective Contraception in Women With Epilepsy
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Over a third of women with epilepsy do not use highly effective contraception, despite the important, negative consequences of unintended pregnancy such as elevated risk of having offspring with congenital malformations. There is a need for more readily available information and counseling on safe and effective contraception for this community.

SCN8A: When Neurons Are So Excited, They Just Can’t Hide It

In this study, researchers identify a set of neurons in the brain as critical targets for therapeutic intervention, utilizing a mouse model mimicking a mutation of the sodium channel gene SCN8A found in 14 individuals with epilepsy. These individuals had seizures that began in the prenatal or infantile period as well as severe verbal delays. The researchers report that this mutation resulted in seizures in both juvenile and adult mice, suggesting that successful therapy would require lifelong treatment.

Epilepsy Research UK (ERUK) Fellow Awarded Prestigious MRC Grant To Investigate Dravet Syndrome

2017 ERUK Fellow Dr Gabriele Lignani, has been awarded a New Investigator Research Grant, worth nearly £700,000 by the Medical Research Council (MRC), to investigate the potential use of gene therapy in Dravet syndrome. This research project will build on Dr Lignani’s ongoing fellowship research – GeneLoop, which is currently investigating the potential of gene therapy as a treatment for acquired intractable epilepsy.

Dravet Syndrome is a severe and extremely rare but catastrophic neurological disorder affecting young children (approximately 1 in 19,000 people). Every day 3 or 4 children are diagnosed with Dravet syndrome worldwide, with symptoms including epilepsy, autism, movement disorders, and sleep disturbances. To date, the majority of therapies are ineffective or poorly tolerated. Sodium channel drugs, which are some of the most commonly prescribed and effective antiepileptic drugs may even worsen Dravet syndrome.

Dr Lignani said: “This research will be useful not only to understand if a permanent general treatment for Dravet syndrome is achievable, but will also give insight into the potential of the techniques to cure other neurological conditions caused by similar mutations in different genes.”

He continued “This research will be useful not only to understand if a permanent general treatment for Dravet syndrome is achievable, but will also give insight into the potential of the techniques to cure other neurological conditions caused by similar mutations in different genes.”

Dr Lignani’s ERUK Fellowship officially began in 2018 but is already showing promising results. His team’s work thus far has focused on developing and testing their gene therapy tools, and they have found that this tool is able to subdue neurons during epileptic activity. The following stages of the fellowship will involve trialing these tools in models of acquired intractable epilepsy.

Use of Next-Generation Sequencing Panel as First-Tier in Diagnostic Process May Enable Precision Medicine

Objective: Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy.

Methods: Researchers used a multi-gene next-generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy-related genes in 9,769 individuals. Clinical variant interpretation was performed using a semi-quantitative scoring system based on existing professional practice guidelines.

Results: Molecular genetic testing provided a diagnosis in 14.9-24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single-nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications.

Significance: Using a next-generation sequencing panel with key high-yield genes and robust analytic sensitivity as a first-tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.

Encoded Therapeutics Bags $104M to Propel ‘Precision Gene Therapy’ for Dravet Syndrome

Encoded Therapeutics reeled in $104 million in series C cash to bankroll the development of its lead program: a precision gene therapy for Dravet syndrome, a rare form of epilepsy. The Bay Area biotech will also use the funds to push its preclinical programs and come up with new treatments for severe genetic disorders.

The company’s work is based on a platform designed to overcome hurdles it has identified in the gene therapy space. Gene therapies tend to work in one of three ways: They deliver a healthy copy of a faulty gene, introduce a new gene into the body or “knock out” a defective gene. But they can run into problems with cell selectivity, potency and the ability to control endogenous genes, Encoded CEO Karthik Ramamoorthi, Ph.D., told FierceBiotech.

“We’ve developed a series of technologies that are both computational and genomics- or sequencing-based that allow us to screen for and identify sequences in vivo that control where and when genes are able to be expressed,” Ramamoorthi said. “We take these sequences and place them in gene therapies—such as adeno-associated viruses (AAVs)—that allow us to control where the adeno-associated viruses are able to express the payload.”

Clinical Evolution and Epilepsy Outcome in Three Patients with CDKL5-Related Developmental Encephalopathy

Objective: To further characterize CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy.

Results: Researchers describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of “honeymoon periods”, as well as EEG features. The “honeymoon period”, defined as a seizure-free period longer than two months, represented, in this case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the “honeymoon period”, the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development.

Significance: These findings suggest that CDKL5 mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.