Metabolic Enzyme Deficiency
Exploring the diversity of metabolic enzyme disorders in the human population
Glafabra is focusing on using cellular gene therapies (CGTs) to address enzyme deficiency disorders in patients. More than half of the genes involved in human metabolism (1546 genes via KEGG hsa011000) can cause a disease when they are absent. Of these, 909 genes are seen in ClinVar database with at least one pathogenic variant, of which about 500 have pathogenic variants that manifest early in life - the child would not survive to adulthood without intervention.
The average yearly incidence rate of these childhood genetic diseases is estimated to be near 1 in 68,000. Cumulatively across the 900+ disease genes, the yearly incidence rate of pathogenic viariants is 0.74% of the population. So, even though the rate of debilitating disease is less than 1 per 100 persons born, the calculation across the planet suggests that about 2 persons are born every second with one of these rare childhood metabolic disorders. That means over 60 M persons are born each year with life threatening childhood metabolic disorder and each gene-specific patient population has average of 120,000 persons.
Metabolic Statistics
>1500 genes in human metabolism.
909 metabolism genes are disease associated (60% of total)
~500 metabolic disease genes are childhood lethal without intervention (30% of total).
Average yearly incidence per gene of pathogenic variant is 1.5 persons per 100,000.
Cumulative average incidence for all 500 genes is 735 per 100,000 (or 0.7% of population).
2 persons born every second with a metabolic disease that is life threatening.
60 M persons per year are affected by life threatening metabolic disorder.
120,000 persons afflicted per metabolic gene.
For the first 25 genes with the highest numbers of variant variety (as detected in ClinVar), the prevalence rate is often known. Additionally, the severity is also available. This allows us to derive the yearly incidence rate for each gene. Also we can estimate the number of genes involved in life threatening metabolic disorder (in red below). These are the genes where a pathogenic variant often leads to early death in adolescence or earlier.
Top 25 Enzyme Deficiency Disorder Genes
At Glafabra, we use LentiVector cellular gene therapy (LV-CGT) to treat metabolic enzyme deficiency in patients. We initially focus on the metabolic disorders that interact with the hematopoietic (blood) system. First, we harvest the patients cells by apheresis of their blood. We next use a LentiVector to on the harvested cells to introduce a working gene copy of the missing enzyme. The result is a set of genetically-engineered cells that can be reintroduced back into the patient where they engraft and start producing the missing enzyme. In our LV-CGT Fabry trial conducted in Canada, the patients achieved sufficient expression of the introduced alpha galactosidase sequence to enable them to elect to stop the tedium of enzyme replacement therapy (ERT). One transfusion gave them 5 years (and counting) of durable relief, instead of needing repeat transfusion every few weeks throughout their life.
Cell Therapy Approach
In summary, there are a variety of genes involved in metabolic enzyme deficiency (>1500). A majority of these genes (~500) have severe to lethal outcomes in pediatric populations. Glafabra is focusing on using a LV-CGT therapy to durably restore metabolic enzymes in patients so that they can have the freedom to live their life unencumbered by biweekly ERT.
A quote from one of the patients in our Canadian trial: