News and Reports

Additional Funding for Previously Funded RDMM Projects

July 13, 2017

RDMM is announcing a call for applications for investigators who would like to apply for additional funds for previously approved projects. Many of the projects that have been funded have reached the one year mark and RDMM will consider awarding additional funding for a subset of those projects with very promising results and a clear set of new and important deliverables that will advance the overarching objectives of the RDMM.


Details

  • Funding Level: $25,000
  • Eligibility: Applications may be submitted by any investigator who has already been awarded a catalyst grant from RDMM. Generally, applications should be submitted after completion of the 12-month term of the initial catalyst grant, but will be accepted as early as 9 months after the start of the initial catalyst award if justified.
    NOTE: *NOTE: Investigators who have secured funds from another source, other than a match, for this project (ie. CIHR) are not eligible to apply.
  • Submission Deadline: No deadline. Applications will be received on an ongoing basis.
  • Application process: Please submit an Application for Renewal of RDMM Catalyst Grants. Submit applications to the RDMM Network at info@rare-diseases-catalyst-network.ca. Decisions will generally be available within two (2) weeks.

* UPDATED: Jan 2017 | Dravet.ca and the RDMM open call has been extended.

October 6, 2016

Dravet.ca is a network dedicated to supporting individuals and families affected with Dravet Spectrum Disorder and promoting research so that one day there may be an effective treatment to prevent the disabilities associated with this disorder or perhaps a cure. RDMM and Dravet.ca are calling for proposals utilizing a model organism approach to investigate disease pathogenesis to inform therapeutic strategies related specifically to Dravet Spectrum Disorder.


Details

Funding Level: $25,000
Duration: 1 year
Eligibility: Applications may be submitted by any investigator associated with a Canadian Institution.
Research Criteria: This application is intended to specifically study the disease mechanism of Dravet Spectrum Disorder, the results of which may ultimately provide insight into therapeutic strategies. The research approach should include the use of a relevant model organism. The proposal can revolve around the gene mutated in 75% of cases, SCN1A, genes more rarely implicated in the disease (SCN1B, SCN2A, SCN8A, GABARG2, GABRA1, PCDH19, CHD2, STXBP1), or newly identified genes or modifiers. Examples of questions to address in animal models could be:

  • Could animal models shed light on genotype-phenotype correlations?
  • What are the best available therapies for each genetic defect and can we identify new therapies?
  • Is the defective GABAergic inhibitory interneuron hypothesis the best explanation for the disease pathophysiology, or is there an overexcitability of glutamatergic neurons?
Application process: A Gene Application to Engage a Model Organism Researcher may be submitted to the RDMM Network at info@rare-diseases-catalyst-network.ca. Funding decision timeline is approximately 4 weeks.
Submission Deadline: December 15th, 2016 at 5 pm EST
* The deadline for the RDMM/Dravet Open Call has been extended. The new deadline is March 31st, 2017.

2017 RDMM/Fondation du Grand Défi Pierre Lavoie (FGDPL) Open Call for Applications

January 18, 2017

Fondation du Grand Défi Pierre Lavoie (FGDPL) is an organization that supports research on rare genetic disease and promotes healthy lifestyles for all. In this open call, RDMM is partnering with FGDPL for proposals utilizing a model organism approach to investigate disease pathogenesis and/or to inform therapeutic strategies related specifically to mitochondrial disorders.


Details

Funding Level Two projects to be funded at $25,000 each. 
Eligibility Applications may be submitted by any investigator associated with a Canadian Institution.
Research Criteria

This application is intended to specifically study the disease mechanism of Mitochondrial Disorders, the results of which may ultimately provide insight into therapeutic strategies.  The research approach should include the use or the generation of a relevant model organism. The proposal can revolve around an unpublished candidate gene, or genes previously associated with mitochondrial diseases in humans (especially if recently identified or studied in Canada). Examples of questions to address in animal models could be:

  1. What are the best available therapies and can we identify new therapies?
  2. What are the various pathways affected by the genetic defect?
Application process

For clinicians, please submit a Connection Application.
For model organism investigators, please submit a Gene Application to Engage a Model Organism Researcher.

Submit applications to the RDMM Network at info@rare-diseases-catalyst-network.ca. Funding decision will be returned in mid-May at the latest.
Submission Deadline March 31st, 2017

 

Congratulations to Dr. William Foulkes and Dr. Jose Teodoro on their catalyst grant!

January 18, 2017

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Drs. William Foulkes (McGill University, Lady Davis Research Institute) and Jose Teodoro (McGill University).


About the Project:

Dr. William Foulkes and his colleagues at the Lady Davis Research Institute in Montreal have been studying familial cases of malignant ovarian germ cell tumours (mOGCT). These are cancers of the upper female genital tract that account for approximately 5% of all ovarian malignancies. mOGCTs are found in girls and young women and although cure rates are high, the incidence of lymph-node metastasis is considerable in clinical stage I and II. Additionally, in patients with advanced disease prognosis is relatively poor, with treatment failure in at least 25% to 30%. There is a clinical need to innovate to develop more aggressive and effective therapies for this cancer. In an effort to define the genetic basis underlying mOGCT, Dr. Foulkes performed whole exome sequencing of eight families that displayed predisposition mutations that predispose families to development of mOGCT. Two of these families carried mutations in the CDC20 gene, which encodes a critical protein required for cell cycle regulation.

With the catalyst grant, Dr. Foulkes will collaborate with the lab of Dr. Jose Teodoro to create a mouse model of mOGCT that carries similar mutations that were identified in the mOGCT families. CRISPR/Cas9 gene editing technology will be used to create the mutations directly in mouse zygotes. It is hoped that these mutant strains of mice will provide a better understanding of the molecular details of how CDC20 mutations cause ovarian cancer and potentially provide an animal model to investigate new treatments for this malignancy.

Congratulations to Drs. Foulkes and Teodoro!

Congratulations to Dr. Johane Robitaille and Dr. Jason Berman on their catalyst grant!

January 18, 2017

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Drs. Johane Robitaille and Jason Berman (Dalhousie University).


About the Project:

Dr. Robitaille, in collaboration with the IGNITE team at Dalhousie University, has identified two potential new genes for the blinding disorder familial exudative vitreoretinopathy (FEVR). FEVR is characterized by failure of the normal vascularization of the retina that leads to secondary neovascularization and scarring resulting in retinal detachment and loss of vision. There is no treatment to address the underlying pathology. Dr. Berman at Dalhousie University will construct zebrafish models to both determine if the mutations in the novel genes are causal and screen for effective therapies. Dr. Berman constructed a zebrafish model of another novel FEVR gene identified last year by Dr. Robitaille’s team, which was also funded by a catalyst grant from RDMM.

Congratulations to Drs. Robitaille and Berman!

* UPDATED: Jan 2017 | Dravet.ca and the RDMM open call has been extended.

October 6, 2016

Dravet.ca is a network dedicated to supporting individuals and families affected with Dravet Spectrum Disorder and promoting research so that one day there may be an effective treatment to prevent the disabilities associated with this disorder or perhaps a cure. RDMM and Dravet.ca are calling for proposals utilizing a model organism approach to investigate disease pathogenesis to inform therapeutic strategies related specifically to Dravet Spectrum Disorder.


Details

Funding Level: $25,000
Duration: 1 year
Eligibility: Applications may be submitted by any investigator associated with a Canadian Institution.
Research Criteria: This application is intended to specifically study the disease mechanism of Dravet Spectrum Disorder, the results of which may ultimately provide insight into therapeutic strategies. The research approach should include the use of a relevant model organism. The proposal can revolve around the gene mutated in 75% of cases, SCN1A, genes more rarely implicated in the disease (SCN1B, SCN2A, SCN8A, GABARG2, GABRA1, PCDH19, CHD2, STXBP1), or newly identified genes or modifiers. Examples of questions to address in animal models could be:

  • Could animal models shed light on genotype-phenotype correlations?
  • What are the best available therapies for each genetic defect and can we identify new therapies?
  • Is the defective GABAergic inhibitory interneuron hypothesis the best explanation for the disease pathophysiology, or is there an overexcitability of glutamatergic neurons?
Application process: A Gene Application to Engage a Model Organism Researcher may be submitted to the RDMM Network at info@rare-diseases-catalyst-network.ca. Funding decision timeline is approximately 4 weeks.
Submission Deadline: December 15th, 2016 at 5 pm EST
* The deadline for the RDMM/Dravet Open Call has been extended. The new deadline is March 31st, 2017.

Congratulations to Robert Hamilton, Yoav Bolkier, James Dowling & Ian Scott on their catalyst grant!

June 9, 2016

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Drs. Robert Hamilton, Yoav Bolkier, James Dowling & Ian Scott (Hospital for Sick Children)


About the Project:

Hypoplastic Left Heart Syndrome (HLHS), in which the left heart is severely underdeveloped, remains one of the most challenging congenital heart lesions for management by pediatric cardiovascular specialists. HLHS occurs in 1 out of 4,000 live births, for an estimated incidence of 2000 cases per year in North America. Newborns with HLHS face a series of cardiac surgeries leading to either a palliative surgical Fontan procedure (wherein venous blood bypasses the heart and drives lung blood flow directly) or heart transplantation. Only 70-80% of HLHS patients survive, and a significant proportion have residual neurological challenges (either intrinsic to the condition or as a consequence of repeated complex congenital heart surgeries) as well as exercise intolerance and heart failure complications.

Hypoplastic Left Heart Syndrome (HLHS), in which the left heart is severely underdeveloped, remains one of the most challenging congenital heart lesions for management by pediatric cardiovascular specialists. HLHS occurs in 1 out of 4,000 live births, for an estimated incidence of 2000 cases per year in North America. Newborns with HLHS face a series of cardiac surgeries leading to either a palliative.

The causes of HLHS remain largely unknown, but there is strong evidence for heritability in some studies, and several associated gene defects are already identified. Recurrence increases from 2-4% after one child to 25% in families with two affected children (suggestive of autosomal recessive inheritance, which has also been demonstrated in early case series and reports). Drs. Hamilton & Bolkier have identified a family where distantly related parents had two offspring with HLHS, and identified an underlying homozygous mutation of a gene expressed in left ventricular tissue and implicated in embryonic development.

With collaborators with expertise in animal modeling (zebrafish: Dr. James Dowling) and cardiovascular embryology (Dr. Ian Scott), they will develop gene-edited models of this identified mutation and assess the effects on underlying left-right patterning and cardiac development, identifying the potential pathways and interactions leading to left heart underdevelopment. Identified interactors and downstream signals may provide further candidate genes underlying HLHS, in addition to elucidating the mechanism of abnormal heart development in this condition. They have DNA samples on 95 subjects with isolated HLHS, who will serve as a resource to search for additional candidate gene causes based on any interactions they identify.

Open call for the RDMM/Dravet applications!

January 6, 2016

The deadline to submit applications for the RDMM/Dravet Open Call is approaching! Applications must be submitted before Friday, January 15 at 5:00pm EST.

To apply, a Gene Application to Engage a Model Organism Researcher must be completed. Send your completed application to info@rare-diseases-catalyst-network.ca.


Dravet.ca and the Rare Diseases: Models & Mechanisms (RDMM) Network have partnered together for an open call for applications.

Dravet.ca is a network dedicated to supporting individuals and families affected with Dravet Spectrum Disorder and promoting research so that one day there may be an effective treatment to prevent the disabilities associated with this disorder or perhaps a cure.

In this open call, RDMM and Dravet.ca are calling for proposals utilizing a model organism approach to investigate disease pathogenesis to inform therapeutic strategies related specifically to Dravet Spectrum Disorder.

This application is intended to specifically study the disease mechanism of Dravet Spectrum Disorder, the results of which may ultimately provide insight into therapeutic strategies. The research approach should include the use of a relevant model organism. The proposal can revolve around the gene mutated in 75% of cases, SCN1A, genes more rarely implicated in the disease (SCN1B, SCN2A, SCN8A, GABARG2, GABRA1, PCDH19, CHD2, STXBP1), or newly identified genes or modifiers.

Congratulations to Dr. Dave Dyment and Dr. Steffany Bennett on their catalyst grant!

December 17, 2015

The Rare Diseases: Models & Mechanisms Network is pleased to announce its recent recipients of the catalyst grant: Dr. Dave Dyment and Dr. Steffany Bennett (University of Ottawa).


Phenotypic and biochemical characterization of a CRISPR/Cas murine model of neonatal progeroid syndrome

Dr. Dyment and colleagues have identified two novel variants in one of the anoctamin genes (ANO6) that is likely responsible for a rare form of Neonatal Progeroid Syndrome or Wiedemann-Rautenstrauch syndrome, a disorder classically defined by premature aging, psychomotor delay, and progressive neurological deterioration. To date, several other anoctamin genes have been shown to be responsible for neurological diseases including Miyoshi muscular dystrophy, dystonia (type 24) and a recessive form of spinocerebellar ataxia. ANO6 functions as a bona fide phosphatidylserine (PS) scramblase, responsible for transporting phospholipids between plasma membrane leaflets. This role in phosphatidylserine metabolism is important as it has implications for neuronal survival and differentiation. Preliminary data, and results in collaboration with others indicates that ANO6 is acting as a gain of function mutation that enhances PS exposure at the outer membrane leaflet. They hypothesise that this aberrant PS exposure at the outer leaflet of the plasma membrane is responsible for the varied symptoms seen in this variant form of Wiedemann-Rautenstrach syndrome.

With RDMM support, Dr. Bennett will test whether the ANO6 mutation exhibits this same gain of function results using a CRISPR/Cas9 mouse model. They will carefully assess the phenotype in mice. In addition, Dr. Bennett will plan to profile the PS, oxidized-PS, and glycated-PS lipidomes (acyl, alkyl, and alkenyl linkages) in ANO6+/MT and ANO6MT/MT compared to WT in peripheral and brain tissues. These studies will lay the necessary groundwork to better understand this emerging class of anoctamin-related disease and their role in phosphatidylserine metabolism in the brain and in other tissues during development.

Congratulations to Drs. Dyment and Bennett!

UPDATE: RDMM/Dravet Open Call for Applications

December 2, 2015

* The deadline for the RDMM/Dravet Open Call has been extended. The new deadline is January 15, 2016 at 5:00pm EST. The application form to be submitted for this open call was incorrect. The correct form has been uploaded and can be found here.


Dravet.ca and the Rare Diseases: Models & Mechanisms (RDMM) Network have partnered together for an open call for applications.

Dravet.ca is a network dedicated to supporting individuals and families affected with Dravet Spectrum Disorder and promoting research so that one day there may be an effective treatment to prevent the disabilities associated with this disorder or perhaps a cure.

In this open call, RDMM and Dravet.ca are calling for proposals utilizing a model organism approach to investigate disease pathogenesis to inform therapeutic strategies related specifically to Dravet Spectrum Disorder.

This application is intended to specifically study the disease mechanism of Dravet Spectrum Disorder, the results of which may ultimately provide insight into therapeutic strategies. The research approach should include the use of a relevant model organism. The proposal can revolve around the gene mutated in 75% of cases, SCN1A, genes more rarely implicated in the disease (SCN1B, SCN2A, SCN8A, GABARG2, GABRA1, PCDH19, CHD2, STXBP1), or newly identified genes or modifiers. The deadline for applications is January 15, 2016 at 5:00pm EST, and the award announcement will be made in March.

A Gene Application to Engage a Model Organism Researcher may be submitted to the RDMM Network at info@rare-diseases-catalyst-network.ca.

Congratulations to the Network’s Recent Catalyst Grant Recipients!

October 19, 2015

The Rare Diseases: Models & Mechanisms Network is pleased to announce its recent recipients of the catalyst grants.

Hanna Faghfoury & Kathy Siminovitch (University of Toronto, Mt. Sinai Hospital/University Health Network)

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by formation of multiple mucosal telangiectasia and major arteriovenous malfunctions which lead to progressive bleeding, severe morbidity and mortality. About 80% of HHT cases arise from gene mutations that lead to aberrant transforming growth factor β (TGFβ) signaling in endothelial cells (ECs), but 20% of cases are of unknown genetic cause. Dr. Faghfoury’s group has recently used whole exome sequencing to search for a disease-causal mutation in an HHT family in which affected individuals lack mutation in any of the known HHT genes. This approach allowed them to identify a missense mutation that maps within a gene not previously implicated in HHT and that fully segregates with disease in this family. They have also carried out preliminary biological studies that demonstrate an adverse effect of this mutation on the corresponding protein’s function in endothelial cells. Dr. Faghfoury will be collaborating with Dr. Siminovitch, who will further define the molecular and cellular pathways that connect this gene mutation to HHT, initially using in vitro cell systems, but primarily through the development and characterization of a new HHT mouse model in which Crispr/Cas9 genome editing enables expression of the mutant protein, definition of its effects on vascular integrity and biology in vivo, and discovery of new therapeutic targets.

Guy A. Rouleau, Patrick A. Dion, Jean-François Schmouth & Jeffrey Mogil (McGill University)

Background: Pain is defined as the following: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Hence the feeling of pain reflects a state of our body in which tissue damage has been (or might be) caused. The premise of this existence is to protect us from irreparable damage to our body. But what happens when pain sensation is absent? When do we become insensitive to pain? This situation usually results in disorders that exist in congenital forms in general population and the study of these disorders has been the focus of the team of Drs. Rouleau, Dion & Schmouth. They are particularly interested in a disorder named Hereditary Sensory Neuropathy Type II (HSANII) which is characterized by a loss of perception to pain, touch, and heat due to partial degeneration of peripheral sensory nerves. This condition appears within the first decade of life in the affected individuals and results in severe debilitating complications including ulcerations, infections, muscle atrophy and amputation of digits.

Dr. Rouleau and his team reported truncating mutations in five different Canadian families of a novel gene pertaining to HSANII, namely referred as WNK1/HSN2. Additional mutations in a neuronal isoform of KIF1A/25B were found in HSANII patients of unknown etiology. Further investigation demonstrated that KIF1A/25B interacts with WNK1/HSN2 at the protein level. Hence the current research project will focus on understanding the relationship between these two proteins in regard to HSANII. For this particular purpose, they are currently developing a “humanized” mouse model of Kif1a/25b that contains the equivalent human deletion into the mouse genome. They will use this mouse model to evaluate the implications of a truncating mutation in the Kif1a/25b isoform at the biological level, and the resulting effect on nociception perception will be evaluated in collaboration with Dr. Mogil’s laboratory.

Dr. Rouleau and his team expect that there will be a difference in temperature and mechanical sensitivity and/or nociception between wild-type and Kif1a/25bdelT/delT animals. If an effect is found in Kif1a/25bdelT/delT animals, they will have generated the ideal model in which to test drugs to prevent this loss of perception to pain. It is possible that there will be no strong HSANII phenotype in these mice. In any event, even if the phenotype is disappointingly mild, these Kif1a/25bdelT/delT animals will be key elements in further elucidating the biochemical and physiological role of this isoform.

Kym Boycott (CHEO, University of Ottawa), Marie-Andree Akimenko (University of Ottawa) & Michel Leroux (Simon Fraser University)

Background: The Care4Rare Team in Ottawa, led by Dr. Boycott, has identified a new gene involved in organizing the body axis. Establishing the left and right sides of the body during fetal development is a complicated process involving the products of many genes and collectively the diseases that result from dysregulation of this process are called ‘ciliopathies’. Using exome sequencing, mutations were identified in a novel gene that causes situs inversus and complex heart defects in two families. These mutations are predicted to disrupt ciliary function. To further investigate the role of this protein, Dr. Akimenko and her team will develop a knockout zebrafish model using CRISPR technology to recapitulate the phenotype. Phenotyping of the mutant zebrafish will be performed at several levels including gross morphology and examination of the structure and motility of cilia. In addition to zebrafish, Dr. Leroux and his team will study the gene function in Trypanosoma, an unicellular parasitic flagellate protozoa, specifically its role in the intraflagellar transport of the dynein complex. Together these experiments in model organisms will provide further insight into the role of this protein in human development and disease.

Kym Boycott (CHEO, University of Ottawa) & Marie-Andree Akimenko (University of Ottawa)

Background: The Care4Rare Team in Ottawa, led by Dr. Boycott, has identified a new gene involved in brain development. Using exome sequencing, a homozygous deletion was identified in a novel gene in a child with dysmorphic features, developmental delay, microcephaly, hypotonia, seizures, and failure to thrive. Using the matching service, GeneMatcher (www.genematcher.org), they identified an additional patient with mutations in the same gene and an overlapping phenotype. To further investigate the role of this protein, Dr. Akimenko and her team will develop a knockout zebrafish model using CRISPR technology to recapitulate the phenotype. Phenotyping of the mutant zebrafish will be performed in the affected organ systems including skeleton, muscle and central nervous system. If the analysis reveals that the zebrafish KO mutant is a good model for the condition, the mutant zebrafish could be used in a high throughput screen to identify small molecules that might treat aspects of the disease. These experiments will provide further insight into the role of this protein in human development and disease.

Congratulations to Dr. Jan Friedman and Dr. Daniel Goldowitz on their catalyst grant!

July 31, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Jan Friedman and Dr. Daniel Goldowitz (UBC).

Background: The disease under study is a rare autosomal recessive epileptic encephalopathy characterized by recurrent perinatal-onset seizures that are resistant to conventional anticonvulsant treatment but respond well to administration of vitamin B6. Most affected children suffer also from developmental delay and moderate to severe intellectual disability along with variety of structural brain abnormalities. The phenotypic spectrum may also include non-neuronal features like hypoglycemia, hypothyroidism, profound electrolyte disturbances and diabetes insipidus in some patients.

The need for a disease model: Despite discovery of the genetic cause which encodes an enzyme important in a brain biochemical pathway, many questions regarding its biology remain unanswered. Little is known about the role of the genetic defect in the pathogenesis of the observed brain structural abnormalities and ultimately the neurodevelopmental impairments. Moreover, the current state of knowledge does not provide a mechanistic link between the enzyme deficiency and some of the extra-neuronal symptoms seen in patients. Understanding the underlying pathophysiological mechanism is important to devise better therapeutic interventions. Progress in this field has been hampered mainly by two factors: difficulty in studying CNS metabolism directly in patients and the lack of an appropriate animal model. Development of an appropriate mouse model for this disease, as proposed here, will provide a platform for research that will fill these knowledge gaps and pave the way to identify new therapeutic strategies for disease modification to improve developmental outcomes in children affected with this inborn error of metabolism.

Research plan: The mouse model will be produced at the Mouse Animal Production Service (MAPS) core facility at UBC (led by Dr. Elizabeth Simpson) through microinjection of a commercially available embryonic stem cell (ESC) line with a conditionally-targeted knockout allele for this gene. Phenotyping studies of the mouse will be conducted at Dr. Daniel Goldowitz’s lab at the Centre for Molecular Medicine and Therapeutics (UBC). These will include detailed histopathological examination of the brain, videographic and electrophysiological assessment for seizures, assessment for behavioral and cognitive disturbances, and comprehensive biochemical/metabolomic profiling for disease-associated metabolites. These data will contribute insight into disease pathogenesis. Future studies planned for this collaborative project include therapeutic interventions to test the effect of dietary treatments as well as novel treatments, such as upstream enzyme inhibitors and high-throughput drug screening with small molecules, to reduce secondary toxic metabolites and brain structural abnormalities and to improve neurobehavioural function.

Congratulations to Drs. Friedman and Goldowitz!

Congratulations to Dr. Clara van Karnebeek and Dr. Philippe Campeau on their catalyst grant!

July 20, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Clara van Karnebeek (UBC, BC Children’s Hospital), and Dr. Philippe Campeau (University of Montreal, CHU Ste-Justine).

Epileptic encephalopathies encompass a group of debilitating and potentially life-threatening neurologic conditions. Accurate diagnosis of the underlying cause, especially inborn errors of metabolism, is essential as this allows for targeted treatment, which can prevent brain damage and improve daily functioning and outcomes of affected children. Dr. van Karnebeek and the Omics2TreatID team applied genomic and metabolomic technologies in a 5-year old boy of Romanian descent referred by a European physician, presenting with severe seizures, developmental delay, and unexplained biochemical abnormalities in blood and spinal fluid. Excitingly, the team identified a novel rare neurometabolic disease; this discovery allowed for treatment with nutritional supplements targeting the metabolic defects. The patient’s response is promising; seizures and head growth have improved.

To further understand the disease mechanisms and enhance treatment strategies, Dr. Campeau has received RDMM funding to develop a mouse model for this rare disease, concomitantly trying a tissue-specific knockout and a CRISPR knock-in approach in order to increase the chances one will be viable and display a similar phenotype. Phenotyping of the mice will be done at several levels (neurological, histological and metabolic), followed by application of different therapeutic strategies with elaborate evaluation of response, optimal dosage, and safety. The knowledge generated by this project will enhance understanding of this metabolic epileptic encephalopathy and advance rapid diagnosis, treatment and perhaps in the future prevention.

Congratulations to Drs. van Karnebeek and Campeau!

Congratulations to Dr. Clara van Karnebeek, Dr. Xiao-Yan Wen and Dr. Sarah Hughes on their catalyst grant!

June 26th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Clara van Karnebeek (UBC, BC Children’s Hospital), and Dr. Xiao-Yan Wen (University of Toronto, St. Michael’s Hospital) and Dr. Sarah Hughes (University of Alberta).

Dr. van Karnebeek and the Omics2TreatID team of clinicians and scientists at BC Children’s Hospital, UBC Vancouver performed genomic and metabolomics analyses to identify the underlying cause of a complex condition in a 3-year old boy presenting with severe epilepsy, developmental delay, abnormal bones, blood clotting problems and abnormally formed brain on the MRI scan. Genetic and chemical results clearly pinpointed deficiency of an enzyme important for sialic acid production. The gene encoding this enzyme has never been reported to cause human disease before, but the essential role of sialic acid for normal brain formation and function as well as other organs is well-known. By reaching out to the global research community, we were able to identify 7 other families suffering the same rare disease. To better understand the disease mechanisms at play and most importantly to evaluate therapeutic strategies to replenish the low levels of sialic acid in the affected cells and organisms, model organism studies were clearly needed.

The RDMM connected Dr. van Karnebeek’s team with 2 experts in model organisms:

Dr. Wen will apply his expertise to generate and study nansa and nansb gene mutations in zebrafish, an appropriate model for conditions with morphological and biochemical abnormalities such as these. His team will define their gene expression during development and knockout their gene function using CRISPR technology and study the phenotype, followed by rescue experiments. The next step will be to evaluate different treatments in terms of effectiveness, safety and side-effects, with the goal to increase intracellular sialic acid levels to rescue the phenotype in brain, bone and platelet formation.

Dr. Hughes will establish a humanized Drosophila model for NANs that will express corresponding patient mutations such that the biological effect of these specific mutations can be determined. Her team will focus primarily on the effects in the nervous system and neural/muscular junctions; they will use our humanized flies in a ‘pilot-scale’ screen for potential small-molecule compounds that can alleviate these defects and then test them in the whole animal for efficacy.

This collaborative work is aimed to help affected patients around the world, enhance early diagnosis and treatment through a better understanding of the hyposialyation disease mechanisms, ultimately to improve patient outcomes.

Congratulations to Drs. van Karnebeek, Wen and Hughes!

Congratulations to Dr. Peter Kannu and Dr. Benjamin Alman (Hospital for Sick Children) on their catalyst grant!

June 12th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Peter Kannu and Dr. Benjamin Alman (Hospital for Sick Children).

Studying rare disorders in which fracture repair is impaired, provides a unique opportunity to improve the understanding of fracture healing and design improved therapies for conditions in which bone healing is impaired. Furthermore, identifying and studying the underlying genetic cause of such rare conditions may identify improved treatments for afflicted patients.

Bilateral tibial osteofibrous dysplasia (OFD) is a condition affecting long bones, characterized by abnormal tibial bone architecture and non-healing tibial fractures. No genetic cause for OFD was previously described. Dr. Kannu and team have identified a novel autosomal dominant germline mutation in four unrelated families affected by bilateral OFD. This mutation affects a tyrosine kinase. The resulting protein is missing a segment containing a residue necessary for receptor polyubiquitination and consequent degradation. Preliminary data from affected patient bone samples suggests that both osteoblasts and osteoclasts are affected by this mutation.

Dr. Kannu and team therefore hypothesize the non-healing bone fractures observed in OFD occurs due to a failure of both cell types to remodel bone. Furthermore, they hypothesize that modulation of the receptor tyrosine kinase activity will affect fracture healing - and this approach could be used to help heal fractures in patients with OFD as well as more common causes of delayed bone repair. In this project, they plan to test this hypothesis, using a genetically modified mouse modeling a mutation identical to the human mutation. They have generated the mice using the CRISPR Cas9 guide system and are viable and fertile. Their preliminary data shows that the genetically modified mouse has cortical bone which is thicker than control and its marrow cavity less cellular. To investigate how the mutation interferes with bone fracture repair, fracture healing experiments will be performed in the Dr. Alman’s laboratory at SickKids using the genetic mouse. Fracture repair will be monitored by radiographs and bone samples obtained from the fracture site at selected time points in the healing process for histomorphometry. Bone markers during the healing process will be analysed by Q-PCR. The pilot data will be utilized in a subsequent grant application to study therapies which may be effective in improving fracture healing.

Congratulations to Drs. Kannu & Alman!

The Canadian Organization for Rare Disorders has launched Canada’s Rare Disease Strategy.


The Canadian Organization for Rare Disorders has launched Canada’s Rare Disease Strategy. Read more..

Congratulations to Dr. Raymond Kim and Dr. Brian Ciruna on their catalyst grant!

May 29th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Raymond Kim (University of Toronto, Hospital for Sick Children) & Dr. Brian Ciruna (Hospital for Sick Children).

Dr. Kim, along with Toronto respirologists, David Hall and Sharon Dell, conducted molecular genetic analysis on patients with the ciliopathy, Primary ciliary dyskinesia (PCD). By whole-exome sequencing through the FORGE consortium, they identified two families with no mutation in the 32 known PCD genes, but mutations in two candidate genes listed in the ciliaproteome, a bioinformatic cilia gene database. These genes were confirmed by segregation analysis and follow the loss-of-function mechanism seen in other PCD genes. Dr. Kim has partnered with Dr. Ciruna, a zebrafish biologist, to determine if these genes play a role in ciliogenesis as reflected in their bioinformatic predictions.

Congratulations to Drs. Kim & Ciruna!

Congratulations to Dr. Sandra Farrell and Dr. Nicolas Pilon on their catalyst grant!

May 15th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Sandra Farrell (University of Toronto, Trillium Health Partners) & Dr. Nicolas Pilon (Université du Québec à Montréal).

Dr. Farrell has followed a consanguineous couple who had two fetuses with a unique pattern of congenital anomalies, including a diaphragmatic hernia, short bowel, asplenia and anteverted nares. This constellation has not been described in the literature and is presumed to represent a novel disorder. Whole Exome Sequencing informed by identification of regions of shared homozygosity showed both were homozygous for a missense variant in a novel gene previously described as causing a similar pattern of features in mice that were null knockout mutants. In order to confirm the pathogenicity of the variant and role of this gene in human disease, Dr. Farrell has partnered with Dr. Pilon to create the mutation in a mouse model. If the pathogenicity is confirmed, it would be the first example of a mutation of this gene causing a recognizable pattern of anomalies in humans. If confirmed, early prenatal diagnosis or preimplantation diagnosis becomes feasible for the couple and it would allow for carrier testing of other relatives in their complex pedigree.

Congratulations to Drs. Farrell & Pilon!

Disease and Models Mechanisms features an interview done with Kym Boycott.


Disease and Models Mechanisms features an interview done with Kym Boycott. Read more..

GENETICS is calling out for papers in rare diseases and model organisms.

May 8th, 2015

The Editors of GENETICS would like the journal to be a venue for papers that provide insight into human gene function and disease and advance the understanding of fundamental concepts of genetics. To read more about this, click here.

For more information, contact:
Mark Johnston, Editor-in-chief, GENETICS
Phone 303-724-3201
Fax 303-724-3215
E-mail: Mark.Johnston@ucdenver.edu

Congratulations to Drs. Lehman and Chen!

May 1st, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Anna Lehman (Children’s and Women’s Health Centre of British Columbia) & Dr. Wayne Chen (University of Calgary).

About the project: Sudden cardiac death occurs in about 1 in 20,000 young people. Hereditary disorders affecting the heart’s rhythm are the cause of many of these tragic events. The RYR2 gene has long been recognized as a cause of sudden cardiac death when it is mutated in a manner that increases the flow of calcium between compartments in cardiac cells. Dr. Chen and colleagues have also recently observed an association of sudden cardiac arrest with a type of RYR2 mutation that reduces the flow of calcium in cardiac cells. Dr. Lehman and colleagues observed that people with this type of mutation appear to be at high risk for ventricular fibrillation, which is a term for uncoordinated contraction of the myocardium, showing a typical ECG appearance, and is the most common arrhythmia preceding cardiac arrest. Furthermore, the cardiac muscle in these individuals appears not to have fully matured during development, giving an appearance known as noncompaction. Considering that medical management of people with RYR2 mutations has entirely been focused on those with gain of function mutations, there is now a need to understand the effects of loss of function mutations and study which medications best maintain a safe heart rhythm in these individuals. With funding from the Rare Diseases Catalyst Network, Dr. Chen will establish a mouse line affected with a loss of function mutation identical to one found in humans, and his team will then elucidate the ways in which this mutation affects cardiac rhythm, particularly in response to various pharmacologic agents.

Congratulations to Drs. Lehman & Chen!

Congratulations to Drs. Robitaille and Berman!

April 17th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Johane Robitaille & Dr. Jason Berman (Dalhousie University).

Dr. Robitaille, in collaboration with the IGNITE team at Dalhousie University, has identified a potential new gene for the blinding disorder familial exudative vitreoretinopathy (FEVR). FEVR is characterized by failure of the normal vascularization of the retina that leads to secondary neovascularization and scarring resulting in retinal detachment and loss of vision. There is no treatment to address the underlying pathology. Dr. Berman will construct a zebrafish model to both determine if the mutations in the novel gene are causal and screen for effective therapies.

Congratulations to Drs. Robitaille and Berman!

Biotechnology Focus


Biotechnology Focus has an article titled: “It’s Not Easy Being Rare”, which talks about the challenges of accessing rare disease drugs. Read more..

BIOTECanada

June 12th, 2015

BIOTECanada has released a white paper titled: “The Canadian Rare Disease Therapies Landscape: Bridging Opportunity to Reality” Read more..

Congratulations to Drs. Frosk and Arts!

March 6th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Patrick Frosk (University of Manitoba) & Dr. Heleen H. Arts (University of Western Ontario).

Dr. Frosk has followed a family with multiple children that died shortly after birth due to multiple severe anomalies. The children had no kidneys and their brains were largely replaced by fluid. Research into this combination of problems led to the identification of 6 other cases that have been reported in the medical literature over the last 50 years and this newly described disorder is named HARMS syndrome based on its key features (HydrAnencephaly, Renal dysplasia, Multinucleated neurons, and Syndactyly). There is strong evidence that this is due to a very rare genetic problem and the family is at significant risk of having another child with the same issues. Whole genome sequencing techniques have recently been used to identify the likely cause of this disorder as a specific mutation in a relatively poorly studied gene. In order to prove that this mutated gene is the cause, Dr. Frosk has partnered with Dr. Arts to develop further studies in model systems since the disorder is so rare and difficult to study in humans. This work will allow them to provide the family with effective prenatal or preconception testing options, define risks in concerned family members starting their own families, and help them learn how this gene works which could in theory lead to targeted therapies and provide insights into the early development of the brain and kidneys.

Congratulations to Drs. Frosk and Arts!

Congratulations to Drs. Hegele and Kramer!

March 6th, 2015

The Rare Diseases Catalyst Network is pleased to announce its recent recipients of the catalyst grant: Dr. Robert Hegele & Dr. Jamie Kramer (University of Western Ontario).

Dr. Hegele and Dr. Kramer have been awarded grants for two projects:

The first project involves a family with autosomal recessive nocturnal seizures and developmental delay, in which through whole-exome sequencing, compound heterozygous mutations were found in a novel gene. Dr. Hegele will be working with Dr. Kramer to perform comprehensive neuro-phenotyping of the highly conserved Drosophila ortholog, as there is currently no information regarding the role of this gene in nervous system development or function in any organism. This research will reveal novel functions for this protein in the nervous system. Furthermore, specialized assays to model seizures and developmental delay in Drosophila will allow them to recapitulate the clinical features seen in affected children carrying the mutated gene. Upon detection of a neurological phenotype in Drosophila, rescue experiments will be performed by expression of the human gene in the mutant fly background. This will allow them to assess pathogenicity of the mutation. This study will provide important insights into the molecular mechanisms of disease of developmental delay and nocturnal seizures, and can form a basis for targeted testing of therapies in the future.

The second project involves a family with a disorder that resembles Angelman syndrome that is characterized by developmental delay, abnormal gait, and laughter abnormalities, in which whole-exome sequencing was used to find a homozygous missense mutation in a novel gene. Dr. Hegele will be working with Dr. Kramer to use cell models and fruit flies to determine the pathogenicity of the identified missense mutation. Expression of recombinant fluorescent wild type and mutated gene will allow them to assess whether the mutation induces a mislocalization of the protein in neuronal cells. They will further evaluate whether or not axonal and cognitive defects in Drosphila mutants with a dysfunctional gene ortholog can be rescued by introducing the wild type and mutated human gene under study. By providing support for the pathogenicity of the detected mutation, they will improve genetic counseling options in the affected family and in additional families with similar phenotypes.

Congratulations to Drs. Hegele and Kramer!

The first Rare Diseases Catalyst Network Grant has been awarded!

February 3rd, 2015

The Rare Diseases Catalyst Network is pleased to announce that the first recipients of the $25,000 catalyst grant are Dr. Stuart Turvey and Dr. Jason Berman.

Dr. Turvey, in collaboration with clinicians and scientists at The Child & Family Research Institute and BC Children’s Hospital, has identified the genetic cause of a unique clinical phenotype comprising severe atopic dermatitis, markedly elevated peripheral blood eosinophil counts with eosinophilic infiltration of the liver and gastrointestinal tract, hepatosplenomegaly, and failure to thrive. Understanding the function of this gene and the consequences of the mutation is anticipated to identify novel therapies for the affected family and to inform our understanding of blood development and basic eosinophil biology. Dr. Turvey has been partnered with Dr. Berman at Dalhousie University to model this mutation and test new potential therapies in zebrafish.

Congratulations to Drs. Turvey and Berman!

GENETICS Open Access Commentary

November 20th, 2014
GENETICS Open Access Commentary: Understanding Rare Disease Pathogenesis: A Grand Challenge for Model Organisms. Phil Hieter and Kym Boycott. Genetics 198:443-445, Oct 2014.

The application of next-generation DNA sequencing (NGS) technology has brought an unprecedented era of rare disease gene discovery. The potential for clinical benefits is enormous, but how do we translate these gene discoveries into a mechanistic understanding of the disease gene’s function and identification of therapeutic targets? Fortunately, we have model organisms that provide powerful tools for investigating the mechanistic basis of diseases, for identifying and developing potential therapeutic interventions, and for evaluating new treatments. The key to success in such endeavors will be to establish efficient mechanisms for catalyzing connections, collaboration, and cross-talk between basic and clinician scientists. In the October 2014 issue of GENETICS, Brooks et al. present the genetic, functional, and biochemical dissection of a multigenerational X-linked pedigree with syndromic microcephaly. This success story exemplifies the synergy that can exist between a clinical geneticist and a basic science research team to catalyze gene discovery and uncover novel disease mechanisms. Read more. http://www.genetics.org/content/198/2/443.full

Understanding Rare Disease Pathogenesis: A Grand Challenge for Model Organisms.

June 12th, 2015

Understanding Rare Disease Pathogenesis: A Grand Challenge for Model Organisms. Phil Hieter and Kym Boycott. Genetics 198:443-445, Oct 2014. http://www.genetics.org/content/198/2/443.full

From mice to yeast: new network to use model organisms to study rare disease

November 17, 2014
From mice to yeast: new network to use model organisms to study rare disease

What do a mouse, a fly, a zebrafish, a worm and yeast have in common? Together these five organisms hold the keys for scientists to better understand the basic molecular function of genes and specific gene mutations. The Canadian Institutes of Health Research (CIHR), in partnership with Genome Canada, has awarded the Canadian Rare Diseases Models and Mechanisms (RDMM) Network — a first of its kind collaboration —$2.3 million to investigate these molecular mechanisms and advance rare disease research.

Rare diseases are usually not the focus of research laboratories, which greatly limits our ability to discover effective therapies. We can gain insight into most rare human diseases by analyzing the equivalent genes and pathways in experimental organisms, because nature uses the same building blocks to construct organisms such as yeast, worms, flies, fish, mice and humans. This approach will underpin the RDMM Network, which is led by Drs. Phil Hieter, Kym Boycott and Janet Rossant.

Our efforts will build on Canada’s proven leadership in rare disease gene discovery through national engagement,” said Hieter, senior scientist at the University of British Columbia. “We will mobilize the entire Canadian biomedical community of clinicians and model organism researchers to communicate and connect, integrate and share their resources and expertise, and work together to provide functional insights into newly discovered rare disease genes.

The RDMM Network includes all basic science researchers studying gene function in model systems and clinician scientists discovering novel disease genes in Canada. It will study biological mechanisms underlying rare diseases at the levels of genes, pathways and networks by analyzing the equivalent (orthologous) genes in the five model organisms.

The key to success will be increased collaboration between clinicians and scientists as early as possible following the discovery of new gene mutations that cause disease,” said Boycott, senior scientist at the Children’s Hospital of Eastern Ontario (CHEO) and associate professor in the University of Ottawa Faculty of Medicine. “Our goal is to better understand new aspects of human biology and disease and identify therapeutic pathways that might lead to the development of new treatments for rare disease patients.

The RDMM Network, through its scientific advisory committee, will fund at least 24 catalyst projects annually. Its goals are to validate genetic variants that cause disease, advance understanding of disease mechanisms, create the rationale for treatment (e.g., identification of candidate drug targets) and establish longer-term collaborations between scientists and clinicians that will lead to subsequent funding of outstanding laboratory and/or applied research. “Together, with our partners at Genome Canada, the Canadian Institutes of Health Research is proud to support the RDMM network, to advance efforts in rare disease research,” said Dr. Paul Lasko, scientific director of the CIHR Institute of Genetics. “Their work will guide the development and improvement of treatments and therapeutics for the more than 350 million people worldwide who suffer from a rare disease.” In addition to co-leaders Hieter, Boycott and Rossant (The Hospital for Sick Children, University of Toronto), the RDMM Network includes a number of co-applicants from the clinical genetics and model organism communities. Funding is provided by CIHR and Genome Canada.

Models & Mechanisms Network

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