Image: Ticio encadenado by Gregorio Martínez (1547–1598)
Regenerative medicine promises to restore damaged tissues and resolve chronic diseases, yet no therapy has achieved true adaptive repair in humans. Ancient Greeks were as fascinated by the tale of Prometheus, eternally tormented by a regenerating liver and an eagle, as modern day audiences are fascinated by Wolverine’s capacity to heal himself today.
But even though it’s been 3000 years since Prometheus liver was damaged by the eagle, we still haven’t identified a widely accepted regenerative medicine. We are adept at managing symptoms and slowing decline, but none of these medicines are able to elicit repair of damage. And despite technological advances with stem cells, gene editing and biomimetic scaffolds, clinical translation of effects in disease models has been limited. So, why have we failed so far, and what can we do to fix it?
We know that human tissues possess the capacity to repair. The liver uses regenerative mechanisms to ensure it remains at the right size needed to maintain homeostasis in the body.And the ability to turnover tissue, maintain structure and respond to local damage is a core component of organ homeostasis. However, current medical treatments, like antifibrotictreatment for idiopathic pulmonary fibrosis (IPF) do not support alveolar regeneration in lungs and immunosuppressants, like JAK inhibitors or TNFa blockers do not repair erosive damage in RA, and have highly variable effects on mucosal healing in IBD, despite doing an excellent job of controlling symptoms over long-term use,. So, internal organ repair remains elusive despite many attempts to achieve it.
One reason that has been suggested for this failure is that current approaches haven’t worked ‘well enough’. This statement reveals a scientific belief that the only way to get tissue to repair is to remove a pathological signal like inflammation or fibrosis, for example. Indeed, in autoimmunity, this belief has led to the idea that we might be able to effect cures by resetting the immune system altogether. The challenge with this, though, is that repair requires some inflammation and some fibrosis, so by suppressing these processes more and more deeply, we are also suppressing capacity to repair.
But the challenge isn’t just one of philosophy. Let’s say that we had a drug that could elicit repair or regeneration. We would need to show that it could do this in controlled clinical trials. And here we come up against a second barrier. We have to show that we can elicitrepair in humans. Now, repair is a complicated process. It’s hierarchical, encompassing inflammation, proliferation, and remodeling. It occurs in waves, requires multiple cellular, moleculr and structural interactions, and takes time to manifest. This means that measuring it requires sophisticated thinking and methods. Internal organs of the body tend to be inaccessible; we can’t reach in and take things out to observe. Whilst imaging offers a less invasive way to look at internal biological processes, it tends to lack resolution or sensitivity to detect change. For example in IPF hrCT techniques are effective in detecting changes in fibrosis, but lack the cellular resolution to detect alveolar restoration, whilst in RA ultrasound and MRI offer the potential to evaluate erosive repair, although largely only in timeframes extending beyond those feasible in early clinical development.
The result of these methodological challenges is that potential regenerative therapies get pushed into clinical trial designs with endpoints that were conceptualised for demonstrating the potential of conventional medicines. These endpoints prioritize rapid symptom reduction or slowed decline, not restoration. For example, ACR20/DAS28 in RA, and FVC in IPF bothreward suppression but overlook structural restoration, adaptation and repair. Indeed, the former was even chosen specifically because it showed response to the typical treatments of the early 90s, rather than because it reflected burden of disease or progression.8 Even in IBD, where mucosal healing is a recognised treatment goal, the focus remains on CDAI/endoscopic scores, which again favour suppression. Furthermore, these endpoints, which are demanded by regulators for approval, create rigid, rather than adaptive, trial designs which hinder exploration of new mechanisms. Given the timeframe of drug development, and multiplicity of risks, it is not surprising that venture capital in the field tends to similarly favour approaches that fit within the clinical-regulatory paradigm of suppression. However, the net, and sad, result for patients is that new medicines tend to offer incremental improvement instead of the breakthrough innovation they, and perhaps we, as an industry, would like to deliver.
But Istesso aims to deliver the first repair-enhancing medicines. So, how do we address these barriers? From a practical perspective, we need to start by creating multi-dimensional endpoints. So rather than focussing simply on functional assessments, we need to integrate those with histological, or imaging, assessments of tissue repair. And we conduct these studies over a timeframe that enables us to see changes and how repair and regeneration relation to symptomatic change. To do this, given the clinical paradigm, we explore potential for use in combination with agents that elicit the sort of rapid symptomatic relief patients and their clinicians expect. And once we’ve done that, we engage in conversation and consultation with the clinical and regulatory communities to redefine the treatment landscape.
More broadly, we believe that this approach and changes to facilitate them are needed across the regenerative and Healthspan space to enable all developers the chance to deliver truly regenerative medicines. By reforming measurements, trials, regulations, and paradigms, we can test human repair directly, transforming chronic disease management into resolution and extending health for all.
