Pre-Clinical Evaluation of a Myoblast Delivery Product for Muscle Regeneration

Incontinence is a significant unmet clinical need. In the UK, faecal incontinence (FI) is estimated to affect approximately 2% of adults and urinary incontinence approximately 24%. These figures increase to over half of nursing home residents. The combined cost of incontinence is estimated to cost the UK healthcare system £billions per year.

Cell therapy offers a promising solution to restoring the function of sphincter muscles that provide continence. Early clinical studies investigating delivery of a suspension of patients' own muscle precursor cells have reported mixed results, with some studies showing no improvement in muscle function. This is possibly due to the cells being delivered in a sub-optimal condition due to their manipulation outside the body and delivery as a suspension, an unnatural state for a muscle cell. To address this, we have developed novel porous microparticles that muscle precursor cells readily attach to and grow in a healthier manner. Our long-term aim is to use these microparticles as part of a novel regenerative medicine to grow patients' own muscle cells, obtained from a small biopsy from a leg muscle, before delivering them, still anchored to microparticles, into the defective sphincter muscle. The microparticles slowly degrade as the precursor cells integrate with the muscle, forming new functional tissue that will restore continence.

Before we can do this, we need to clearly demonstrate the beneficial effects of delivering cells attached to the microparticles compared with conventional delivery methods. The project will address this firstly by investigating whether the muscle precursor cells attached to the microparticles retain their potential to form new muscle. We will then investigate the ability of the microparticles to retain the muscle precursor cells at the site of implantation and form new muscle.

The data and protocols generated from the project will be used to bridge the translational gap and justify progression of the technology to more extensive pre-clinical testing required before we can start clinical testing of the product as a new type of regenerative medicine in humans to restore continence.

Although incontinence is the clinical condition targeted with the innovative therapy in the current project, the translational gap being addressed will offer a platform technology for other conditions where efficient delivery of cells is likely to be of therapeutic value. This includes conditions such as localized forms of muscular dystrophy or muscle trauma that result in muscle insufficiency, as well as heart failure, neurological disease, bone reconstruction, and healing of chronic wounds. If successful, the therapeutic system will have tremendous economic benefits to the UK NHS, as well as delivering social, economic and psychological benefits to patients.

Incontinence is a significant unmet clinical need for which cell therapy offers an innovative medicine to restore sphincter muscle function. Clinical studies to date using autologous muscle progenitor cells (myoblasts) have been disappointing, probably due to suboptimal manufacture and clinical delivery of the product. Conventional manufacture of autologous myoblasts involves cell isolation from biopsies and culture on substrates not suitable for implantation into the body. The adherent cells require detachment during passaging and prior to clinical transplantation, delivering to the patient a sub-optimal product, i.e. adherent cells in a suspension, which may quickly become non-viable or migrate from the implant site. We propose expansion and delivery of myoblasts attached to biodegradable, clinically approved microparticles. The provision of a temporary degradable substrate will increase the potency of the delivered cells and help retain them at the target site.

This project intends to demonstrate the benefit of delivering myoblasts attached to the surface of TIPS microparticles via greater persistence, retention and engraftment of transplanted cells at the target site compared with cells delivered conventionally in a cell suspension. The quantity of cells delivered will be equivalent to the number used in clinical trials for faecal incontinence. Phenotypic stability and engraftment of the transplanted cells will be investigated, along with an assessment of local tolerance of the microparticles including inflammation, scarring and bioabsorption at the site of implantation over pre-determined time intervals.

If successful, the project will provide unequivocal evidence that delivery of cells anchored to biodegradable microparticles results in greater persistence and retention of viable cells at the implant site and will de-risk subsequent more extensive pre-clinical evaluation of the technology that will be required before clinical testing can begin.

The project will provide impact within the MRC Research Changes Lives strategic plan through delivery of new regenerative medicine products for treatment of disease and translation of projects that require an interdisciplinary approach to get to the point of clinical testing.

Short-term (1-3 years) beneficiaries will include companies in the cell therapy industry, especially those that are beginning to explore the untapped market of faecal incontinence (FI), but also for other indications if safe and efficacious. Autologous myoblasts are already used as advanced therapeutic medicinal products in commercially-sponsored clinical trials for a variety of clinical conditions, notably FI, urinary incontinence, cardiomyopathy, trauma, volumetric muscle loss, and localized muscular dystrophy. However, existing pre-clinical and clinical data indicate improved methods are needed for delivery of cells. The project will provide further evidence of the value of using TIPS microparticles for cell delivery, which will be readily translatable to other cell types and clinical indications. This will attract further partnership or out-licensing opportunities for companies interested in innovative cell therapy products and thus help foster UK economic competitiveness. Development of combined cell based medicinal products is an evolving area of research and guidelines from the regulatory authorities (MHRA and EMEA) are continuing to evolve. The developmental pathway for the project will contribute further evidence for policies within this area. Shared data in terms of research will have a huge impact, with verification of the technology underpinning pre-clinical studies for other conditions.

Mid-term (3-5 years) the programme of research will verify efficacy of the therapeutic system for FI and other clinical conditions. Successful clinical validation of the therapeutic system will reduce the current economic and social burden of incontinence on the UK NHS and patient community. Primary beneficiaries from the project will be patients with FI caused by non-neurogenic damage to anal sphincter muscle (notably from obstetric trauma), but other beneficiaries of the technology will include patients with FI caused by primary degeneration of sphincter muscle. The therapeutic system is of value to other conditions associated with muscle insufficiency. Therefore, the intellectual property relating to further development of the technology holds significant value for commercialisation. Dissemination of the project findings will help underpin a drive for innovative cell-based therapeutic interventions for FI and other clinical conditions, thus boosting the UK economy.

Longer-term (>5 years) after efficacy for repair of overt sphincter damage with the therapeutic system has been demonstrated, we envisage the technology being applied as a prophylactic treatment to prevent the onset of incontinence in patients who have detectable sphincter disruption (based on increased adoption of improved ultrasound imaging technology), but who do not currently experience symptoms.

The project will provide the Post-Doctoral Research Associate with an excellent opportunity to develop interdisciplinary career skills in a multidisciplinary environment as well as gaining an insight into the translation pathway required to translate the novel technology to the point of clinical testing. The project will equip the person with the breadth of skills needed to effectively understand the processes involved in developing new healthcare products and provide them with experience of how to establish links and subsequently work with industrial partners as the technology moves forward. These career development opportunities go beyond those typically offered in a pre-clinical research project and will provide the researcher with key attributes highly sought after for academic-industrial partnerships, adding a skilled scientist to the burgeoning UK med-tech industry work force.