Necrosis is the ultimate cause of irreversible tissue and organ damage following stress, as well as acute and chronic disease. Yet, to date, no viable interventions to block necrosis exist. This translates to limited therapeutics for conditions where necrosis plays a significant role, such as in cardiac arrest, stroke and renal disease. Necrosis has also hindered scientific research and development – for example, in organ preservation and bioengineering.
Necrosis is accidental, non-adaptive cell death (ie it confers no benefit). This contrasts with beneficial forms of cell death that have evolved to aid in wound healing and cancer prevention. Stressors – such as a lack of oxygen and nutrients to cells, due to a blockage or loss of blood flow; oxidative stress; inflammation; temperature fluctuations; and physical injuries – can trigger necrosis. The result is irreparable harm to cells that constitute tissues and organs. This translates to loss of vital tissue and organ function, which, in turn, gives rise to disability and mortality.
To put it another way, necrosis is the reason why a doctor only has four minutes to resuscitate a patient following a heart attack; why a stroke is so deadly; and why insults to the kidney result in the need for dialysis.
Necrosis is also why a heart or lung, once removed from a donor, can only be stored for four to six hours before transplant. It is this storage constraint that is a key contributor to the scarcity of available organs for transplantation; in the US, 17 people die each day waiting for an organ transplant.
Additionally, immune hyperactivity, exemplified by Covid-19-related complications such as chronic obstructive pulmonary disease, exacerbates damage through necrosis. Liver disease, peripheral vascular disease, osteoporosis and neurodegeneration also involve necrosis, culminating in severe health outcomes. More recently, even the stress of microgravity experienced by astronauts during spaceflight has been shown to increase disease risk and to negatively impact physiology through necrosis.
LinkGevity, a biotech company based at the Babraham Research Campus, Cambridge, UK, has developed groundbreaking research that marks a significant advancement in the understanding and treatment of necrosis. Historically, necrosis has been perceived as a random process, lacking a defined molecular pathway. Intervention was believed to be impossible.
However, LinkGevity has uncovered a molecular pathway at the heart of the necrosis process and the company is now developing a new class of inhibitors targeting necrosis. “Our data to date shows that the new necrosis-inhibiting compounds can block necrosis by an impressive 90% in the lab”, says Dr Carina Kern, LinkGevity’s CEO.
This breakthrough has profound implications for disease treatment paradigms. Take acute kidney injury (AKI), for example, a condition that is caused by multiple stressors and for which there is currently no viable treatment beyond dialysis or transplantation.
Previous attempts at treating AKI have focused on addressing individual upstream triggers of the disease, such as inflammation or oxidative stress, yet none achieved comprehensive intervention. Even combination therapies given for some triggers, such as hypoxia (reduced oxygen supply), fall short –there just are no feasible interventions.
LinkGevity's research opens the door to a new therapeutic approach, targeting necrosis, the common downstream pathway to all these stressors (including hypoxia), which has so far evaded medical intervention.
Aside from AKI, these necrosis inhibitors open the door to interventions for other conditions, both inside and outside the clinic, where necrosis has so far proved to be a stumbling block.
“Our areas of immediate focus include organ preservation”, says Dr Kern. “The massive gap between organ supply and demand at the moment is, in large part, due to the difficulty in storing and transporting organs. Once removed from the body, hypoxia often kicks in, causing necrosis.
“Our experiments in small animals already show promise for our drugs effectively blocking necrosis and extending that preservation window. This is really exciting as it could save tens of thousands of lives”.
To find out more about LinkGevity's work, please email info@linkgevity.com
