Translational Drug Discovery

Our translational drug discovery and development program focuses on the identification and development of peptide or protein-based therapeutics for cardiovascular disorders in kidney failure and beyond. Our translational and clinical research teams in the Lim Laboratory work closely together on projects that are inter-related and support each other. This creates a rich environment that fosters internal multi-disciplinary collaborations, and catalyzes breakthrough discoveries and academic entrepreneurship. Our translational program combines techniques in cell and molecular biology, bioengineering and human tissue research. As part of our translational drug discovery program, we have two major interests areas that aligns with our clinical research theme:

1. Identification of myokines with therapeutic potential

Myokines are a diverse group of peptides and proteins that are synthesized and released by skeletal muscle in response to exercise. They have been implicated in mediating the beneficial effects of exercise, and they can function as autocrine/paracrine and endocrine hormones. Their effects are diverse where they can regulate the skeletal muscle itself as well as target distant organs throughout the body to regulate the activity of the cardiovascular, kidney and other tissues. This enables organ cross-talk and their discovery unveils an emerging kidney-cardiovascular-skeletal muscle axis critical to human health. Over 600 myokines have been identified to-date. In the Lim Laboratory, we have identified several myokines that are severely deficient in patients with CKD and may play a major role in the development and progression of cardiovascular and kidney failure. Moreover, our research demonstrates that their replacement in states of deficiency in CKD could potentially prevent or reverse disease development. 

a researcher prepares a sample in the lab


Our drug discovery pipeline utilizes several unique human tissue cohorts that we have developed over the years. We take the approach of integrating our translational wet lab and clinical research efforts, and this stimulates multi-disciplinary collaboration on projects that support each other.

2. Development of peptide-based therapeutics (peptidomimetics)

Delivering myokines or other peptides for therapeutic indications is compounded by several challenges such as short half-life or instability, poor oral bioavailability and low membrane permeability. The field of peptidomimetics enables us to utilize various technologies to create peptide mimics (drugs that are based on naturally occurring peptides) with enhanced stability and bioavailability. Since the discovery of insulin approximately a century ago, over 80 peptide drugs have been developed to treat a wide range of diseases. However, currently in the field of nephrology or cardionephrology, few peptide-based drugs have been developed that can directly target the kidney or complications of kidney failure. Peptide therapeutics represent an emerging and exciting strategy that have a number of potential advantages over chemical-based drugs, such as improved target selectivity and reduced off-target effects. 

 

Accelerating Drug Discovery Using Human Tissues

Our group is home to two human tissue cohorts that provide a robust and unique platform to support our drug discovery and development program:

a researcher uses a microscope in the lim labCAIN Cohort

CAIN stands for Cardiac Aging in Chronic Kidney Disease and is a multi-disciplinary collaborative study to investigate, identify and develop new therapies to target age-associated cardiac changes of the heart that occurs in chronic kidney disease (CKD). CAIN uniquely collected over 120 human heart tissues donated for research purposes from deceased CKD and healthy donors through the National Disease Research Interchange (NDRI). This rare cohort of human heart tissues provides an unparalleled platform to identify novel therapeutic targets. Tissues have undergo next-generation bulk RNA-sequencing, single-cell and single-nuclear RNA sequencing with our collaborative partners.

Vascular Cohort

The vascular study is a rare collection of over 600 human arteries from advanced CKD patients. The collection houses arteries from various vascular beds complete with echocardiographic and applanation tonometry data. This unique resource provides an unparalleled platform to facilitate drug discovery. The vascular cohort development was led in collaboration with Dr. Thomas Hiemstra (Cambridge University) and Dr. Daniel Zehnder (North Cumbria University Hospitals NHS Trust) in the UK.