Inflammatory Diseases and IBD
It is well established that microbes modulate the immune system in multiple ways, contributing to both immune activation, as well as homeostatic regulation. Inflammatory Bowel Disease (IBD) is a chronic and debilitating condition that results from severe inflammation of the gastrointestinal tract. Two conditions, ulcerative colitis and Crohn's disease, account for the vast majority of the 5 million IBD cases worldwide.
A growing body of scientific evidence suggests a causal link between the gut microbiome and IBD. Possible theories range from the activation of the inflammasome through opportunistic pathogens that take advantage of barrier dysfunction to genetic defects within the host that trigger a deleterious response to normally commensal microbiota. There is consensus within the medical community that the microbiome is central to the development of chronic intestinal inflammation and subsequent IBD.
Second Genome is actively investigating microbially-mediated mechanisms underlying IBD. By identifying the bacteria and viruses that play a role in IBD, our research team is aiming to identify new therapeutic approaches and strategies to treating this debilitating condition.
The link between the gut flora and a wide variety of diseases is beginning to be appreciated. Recent interest in the immunomodulatory roles of particular bacterial species within the gut has been highlighted in murine model systems of melanoma. These studies have shown that the effect of the immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1) depend on Bacteroides and Bifidobacterium species subsets in these murine systems. In humans suffering from melanoma, the therapies that generate the most durable responses activate the immune system, but only in a fraction of patients. Recent survival success of the immune checkpoint inhibitors targeting CTLA-4 and the PD-1/PD-L1 axis in patients with melanoma, along with both human and murine data, suggests that certain microbial flora could enhance response to these therapies and offer novel therapeutic avenues.
As an initial discovery step, we combine internally and externally available data to identify microbial signatures that are associated with enhanced response to checkpoint inhibitor therapy. Libraries of peptides, proteins and potential bioactive molecules derived from these strains and other relevant genomic data are empirically tested and screened for binding, function and therapeutic benefit using traditional model systems.
Metabolic Diseases and NASH
A significant body of research suggests that the microbiome is causal in the development of numerous metabolic disorders, including obesity and type 2 diabetes, and nonalcoholic steatohepatitis (NASH).
The worldwide prevalence of obesity and associated metabolic conditions continues to increase rapidly, impacting more than one in five Americans. Emerging evidence suggests that the microbiome is central to metabolic processes and redefines the way we understand this disease and its progression. Recent microbiome transplant studies have demonstrated that the introduction of specific microbes can influence host biology to drive weight loss or gain, suggesting the microbiome is an untapped source for the treatment of obesity. Leveraging our novel drug discovery platform, Second Genome can understand the unique biological interplay between the host and microbiomes to identify potential therapeutic targets to help curb the metabolic disease epidemic.
Estimates from the National Center for Health Statistics suggest that about 2-5% of the US population has NASH, and an additional 10-20% have fat accumulation in the liver, a precursor to NASH. It is projected that NASH will surpass hepatitis C as the leading cause of liver transplant by the year 2020. The exact cause of NASH is not understood, but it often occurs in people who are overweight/obese or have other metabolic conditions such as type 2 diabetes or elevated lipids. As NASH progresses it can lead to liver cirrhosis and death. Currently, there are no approved treatments for NASH.
Central Nervous System Disorders
Recent research has demonstrated a strong link between CNS disorders and the gut microbiome. Our initial project is focused on autism spectrum disorders (ASD). While ASD hs a strong genetic component, it is also believed that the gut microbiome may play a role in the condition. Several studies have examined the gut microbiomes of individuals with autism and support the idea of a strong link between the human microbiome and autism-related behaviors.Second Genome was recently awarded a $2.1M fast-track NIH grant to expand the SG Technology Platform to develop treatments for central nervous system disorders to support the M3 program.