Despite being the leading cause of disability worldwide, lower back pain (LBP) remains poorly managed and treated[1]. To address this unmet clinical need, the Horizon 2020-funded iPSpine consortium was formed to develop an Induced Pluripotent Stem (iPS) cell-based therapy to treat specific LBP related to the degeneration of the intervertebral disc.
Understanding the cause of LBP
Although the cause of LBP is multifactorial, it is widely accepted that a major contributor to back pain is degeneration of the spine’s intervertebral discs (IVDs)[2]. To date, there are no treatments that can halt or reverse IVD degeneration. One potential approach to the issue is the development of mesenchymal stromal cell (MSC)-based therapies. In phase III clinical trials, MSCs appear to decrease pain and improve quality of life but there is no evidence that they achieve tissue regeneration at the structural level leading to a sustained clinical benefit for LBP patients[3].
The iPSpine strategy focuses on generating an iPS-based cellular therapy that can induce regeneration of the IVDs and stop degenerative processes and, as such, also pain[4]. Importantly, the iPSpine cell product will have the potential to rejuvenate the disc tissue, thereby achieving biologic repair of the IVD and ultimately sustained clinical benefits to the patient. These regenerative and anti-degenerative properties are present in notochordal cells. Notochordal cells reside in the core of the disc only during embryonic development and remain present until childhood, after which they disappear and are replaced by smaller disc cells. Hence, adult discs do not contain notochordal cells and there is a clear association between the loss of notochordal cells and the onset of disc degeneration[5].
It is therefore not possible to use the patient’s own notochordal cells (autologous approach), nor can notochordal cells be directly collected and expanded from other adult individuals (allogeneic approach). The consortium therefore developed a strategy to generate notochordal-like cells using iPS technology. Human blood cells are programmed to become iPS cells which can be differentiated into notochordal-like cells or a suitable predecessor cell type[6] and the most recent work of the consortium was presented in several abstract presented during the annual meeting of the International Society for the Study of the Lumbar Spine in Milan 2024[7]. There are plans to generate an iPS master cell bank for further commercial development.
It is the aim of the iPSpine project to develop and characterize the safe iPS-derived, suitable notochordal predecessors that exhibit the desired properties required to rejuvenate the diseased IVD. Safety is investigated by meaningful in vitro and in vivo studies according to relevant EMA guidelines[8]. Proof-of concept (PoC) studies in clinically relevant animal models are being performed to demonstrate that after implantation, the cells differentiate to the desired phenotype and secrete fresh matrix proteins to fill up the lost volume with new tissue of appropriate biomechanical properties4. The advanced stem cells are supported by innovative biomaterials that provide them a safe home to thrive within the harsh disc environment[9],[10]. These innovative biomaterials form a hydrogel and will be injected together with the cells. Once the biomaterial solidifies to a scaffold in-situ, it is expected to keep the iPSpine cells in the right location, protect them from mechanical stress and eventually also support the activity of the targeted phenotype.
The development is covered via six interdisciplinary work packages that are further supported by a work package involving ethical and policy considerations[11]. This involves identifying the ethical and policy challenges of the iPSpine consortium and mapping EU policy governing stem cell research and advanced therapies in regenerative medicine4,[12].
As the regulatory partner, PharmaLex provided support from beginning of the project to all partners, offering consultancy for different areas of development. These included iPSC good manufacturing practice (GMP) set-up, specification development for iPSC and drug substance, nonclinical development program and addressing specific questions, such as the classification of the envisaged product as either a combined or a non-combined ATMP (which is a question related to the role of the biomaterial in the final product). We also conducted training for the consortium to create awareness of the consequences of particular decisions, such as in the setup of specific studies for eventual clinical development, as well as how to reach regulatory milestones and reduce the translational bottlenecks when going from development to treating patients.
One important regulatory milestone for the consortium was the scientific advice with the German Paul-Ehrlich-Institut (PEI) in 2022, during which details on iPSC and drug substance development and specification were discussed, as well as suggestions on nonclinical development and regulatory aspects.
The second important regulatory milestone has been scientific advice with the Swedish Medical Products Agency (MPA) in April 2024, with follow-up discussion to help direct further scientific development of this first of class therapeutic product and the essential follow up funding.
The approach of using IVDs to generate matrix-producing cells with support of biomaterials is still in early development, but important progress has been made by the iPSpine consortium. The next stages of product development will include refinement of explant cultures, understanding mechanisms of action, further characterizing suitable biomaterial candidates, and refining cell culture protocols for suitable GMP production of a potential drug substance.
What research questions are you struggling with, particularly as relates to regenerative, novel therapeutics? We would be interested in hearing about your own research as well as your thoughts on iPSC to address low back pain from IVD degeneration.
About the authors:
Dr Zaklina Buljovcic, Director, Principal Consultant, at PharmaLex is a regulatory specialist for innovative therapies, especially advanced therapy medicinal products with 16 years of experience in the field and 20 years in the regulatory business. She has also broad experience and knowledge with other biotech products like vaccines, microbiota transplantation, natural substances or combinations. She supports clients in overall regulatory strategy, project management and pharmaceutical quality.
Angela Vogt-Eisele is an Associate Director at PharmaLex. She has worked for the pharmaceutical industry for over 10 years supporting non-clinical and clinical development programs and has in-depth experience in the preparation and management of the non-clinical and clinical parts of dossiers, pediatric investigation plans, orphan drug designations, environmental risk assessments, briefing books and other regulatory documents. Angela is regularly involved in communication with health agencies, such as during scientific advice meetings.
[1] The global epidemic of low back pain, The Lancet Rheumatology. June 2023. https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00133-9/fulltext
[2] IPSpine, background. https://ipspine.eu/project/background/
[3] Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain, North American Spine Society Journal (NASSJ), Volume 13, 100195. Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain – North American Spine Society Journal (NASSJ) (nassopenaccess.org)
[4] iPSpine Approach. https://ipspine.eu/project/ipspine-approach/
[5] Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus, Scientific Reports, March 2017. https://www.nature.com/articles/srep45623
[6] In vitro and in vivo models define a molecular signature reference for human embryonic notochordal cells, iScience, Volume 27, Issue 2, 16 February 2024, 109018. In vitro and in vivo models define a molecular signature reference for human embryonic notochordal cells – ScienceDirect
[7] International Society for the Study of the Lumbar Spine, Abstracts and program books 2010-2024. ABSTRACTS AND PROGRAM BOOKS 2010-2024 — The International Society for the Study of the Lumbar Spine (issls.org) g
[8] Guidelines relevant for advanced therapy medicinal products, https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview/guidelines-relevant-advanced-therapy-medicinal-products
[9] Injectable hydrogel induces regeneration of naturally degenerate human intervertebral discs in a loaded organ culture model, Acta Biomaterialia, Volume 176, 1 March 2024. Injectable hydrogel induces regeneration of naturally degenerate human intervertebral discs in a loaded organ culture model – ScienceDirect
[10] Thermally triggered injectable hydrogel, which induces mesenchymal stem cell differentiation to nucleus pulposus cells: Potential for regeneration of the intervertebral disc, Acta Biomaterialia, Volume 36, May 2016. https://www.sciencedirect.com/science/article/abs/pii/S1742706116301258?via%3Dihub
[11] Recognizing the ethical implications of stem cell research: A call for broadening the scope, Stem Cell Reports. 2021 Jul. https://pubmed.ncbi.nlm.nih.gov/34214488/
[12] Mending the Gaps: Ethically Sensitive Cells and The Evolution of European Stem Cell Policy, Regenerative Medicine, 17(8), 581–595. https://doi.org/10.2217/rme-2022-0043
