Organoids in Drug Discovery- a celestial map of Innovation

The launch of new drugs in the market has the solid purpose of fulfilling patient needs. Nowadays, the approval of new drug products depends on evidence of efficacy, safety and quality, reflected in regulatory requirements, which are rules of law to protect individuals.

The grounds for such requirements were only formally set in stone in 1962, under the Kefauver-Harris or Drug Efficacy Amendment, following the unfortunately well-known tragedy caused by the use of Thalidomide as a morning sickness treatment during pregnancy. This amendment made it mandatory not only to prove the safety of drugs, but also to provide evidence on the effectiveness based on adequate and well controlled clinical studies. It also established requirements for compliance with Good Manufacturing Practices and the filling of an adverse events report.

While moving the drug advertisement under the umbrella of the FDA, all the information would be filed for approval and afterwards breaking through the market. The previously 1938 approved Federal Food, Drug and Cosmetic Safety Act already engaged pharma companies in animal toxicology to support the entry of new drugs into the market.

Moreover, as of 1981, the conformity to follow formal standards for the protection of humans (and strengthen of Institutional Review Boards, IRB) has become more stringent (Federal Register 8980 Volume 46, Number 17). The drug sponsor had to start showing:

  • Results of preclinical testing
  • The purpose of the studies and tests in humans

Everything started to be wrapped up in the so-called Investigational New Drug Application (IND). This document connects and gathers all the data throughout the long lastly procedure of pre-clinical drug development. The data included in the IND needs to be generated from different sources, and includes efficacy and safety information from in vitro and in vivo (animal models) models. Along Chemistry Manufacturing and Controls (CMC), this document is the foundation of balancing risks and benefits to humans, supporting the initiation of first-in-human studies.

Overall, the IND procedure assures that the efficacy, safety and quality will be met as an investigational drug. Still, these three criteria are a never-ending assessment, even after reaching the market [1].

 Historical perspective

Understanding the anatomo-physiology of organs has always been one of many fundamental questions of Human Medicine. That knowledge underlies the understanding of the molecular and cellular counterparts of homeostasis of organ function and the mechanisms disrupting its normal physiology, which are the basis for the development and design of new and better drugs. Additionally, these aspects are paramount to study in depth the formation of organs, fulfilling the quest for the design of human organs for transplantation purposes. Ultimately, providing chronic organ failure patients with solutions that increases drastically their quality of life.

Consistent research efforts supporting the development of organoids, organized cellular structures in a Petri dish, have more than one century. The precluding steps were taken back in 1907, when Henry Van Peters showed in sponge cells that physical dissociated cell lines could then be spontaneously reorganized generating an organized organism.

The corollary of all the basic research being performed in the fields of Stem cells as led to:

  • The generation of a vascular liver organoid in 2006
  • Proto-organoid of neuronal cells by 2008 (cerebral organoids in 2013)
  • Intestine organoids structures in 2009
  • The first renal organoids conceived from murine cell lines in 2010
  • In 2014, cardiovascular human organoids were generated in research labs, among many other major achievements.

We come this far to have gained the information, knowledge and wisdom to generate a multitude of 3D organoids. In very simple terms, we start by the collection of fibroblast cells from humans, then undifferentiated to Induced Pluripotent Stem Cells (iPSC) and further differentiated into a specific type of Organ (Heart, Liver, Lung, Kidney, CNS, Gastro-Intestinal, you name it).


Current trends

Certainly, one out of many practical applications of Organoids is to test new drugs for both safety and efficacy parameters. What are the advantages and capabilities of Organoids in new drug development?

  • Gathering Human-derived data earlier in the R&D process – since human organoids represent human physiology, rather than being a ‘human-like’ or ‘similar’ system;
  • Relatively rapid method – adult stem cell-derived and pluripotent stem cell-derived organoids can be established rapidly and consistently;
  • Process robustness – once established, scale-up is usually possible for large-scale genomic and drug screening activities;
  • Genetic manipulation – most modern genetic engineering tools can be applied to induced pluripotent stem cells or directly to organoid systems;
  • Reaching personalization – induced pluripotent stem cells and organoids can be obtained from individuals and mimic specific phenotypes [2].


Preclinical toxicology is a supporting tool to estimate safety therapeutic windows and to provide a general picture on the toxicology profile. Hence, exposing the drug development sponsor to unaware safety and tolerability risks. Organoids is one of the technologies driving the way to better toxicology profiling of drugs before the first-in-humans studies. Namely on:

  • Comprehensive understanding of toxicity mechanisms;
  • Overcoming interspecies variability;
  • Smoother translation of drugs from preclinical to clinical stages

On and on, leading to a stronger prediction of safety events, mitigating risks connected to unexpected side effects. Even supporting the development of biomarkers as surrogate clinical endpoints to a fiduciary safety and tolerability of investigational drugs [3].

Future trends

The industrialization of Organoids in drug development is in its aftermath. Some trends in the near term could eventually encircle the following:

  • In the short-medium term we will certainly move towards complex organoids composed of a multitude of cell types, being closer to full human resemblance, offering the right milieu to test new drugs;
  • The regulatory landscape will be highly supportive of defined standard enabling a consistent, effective and rationale use of this technology;
  • Technology enablement applied to Organoids will foster new analytical methods and capabilities to a leaner drug development approach. Especially when crossing it with:
  • Imaging technologies that will bring forth accurate in situ Pharmacokinetic and Pharmacodynamic insights in a continuous way;
  • Computational and Mathematical modelling that will yield methods to integrate and process in a consistent manner tons of data beyond human capability;
  • Multiomics methodologies (Genomics, Transcriptomics, Metabolomics, Proteomics) for a non-stochastic and unbiased drug discovery path;
  • Other technologies, since no one has a crystal ball to predict the future.

AccelBio Organoids

The AccelBio leitmotif is exCell the patient mission. Our commitment is mirrored in a vertically integrated R&D approach (target validation, hit identification, lead optimization and early ADMET), offering the possibility to streamline drug design and translation via our R&D Quality by Design approach applied to Organoid systems (CNS, Cardiovascular and Kidney).

We would love to hear your views on the topic. Connect and partner with us! Find us through our website and social networks (LinkedIn, Twitter and Instagram).

[1] https://www.fda.gov/files/Promoting-Safe-and-Effective-Drugs-for-100-Years-%28download%29.pdf

[2] https://www.nature.com/articles/s41580-020-0259-3

[3] https://www.nature.com/articles/s41573-022-00633-x


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