Stem Cell and Gene Delivery

An update

Ambikanandan Misra,  Professor, Pharmacy, Faculty of Pharmacy The Maharaja Sayajirao University of Baroda

These days, gene and stem cell therapies have the potential to make the substantial impact on the treatment of several diseases. However, there are pros and cons of each strategy, but the optimal selection of gene delivery vector or stem cell may often lead to better therapeutic effect.

This years, the interest in stem cell and gene-based therapy showed from industries and spinout companies have been exceptional which reflects the growing confidence in the field grounded on frequently reports of the therapeutic efficacy and the licensing of stem cell and gene-based therapies. Yet, stem cell-based therapy remains in its early stages, akin to gene delivery two decades ago. However, some of the important delivery aspects and updates on the delivery of stem cells and genes are discussed herewith.

Pluripotent Stem Cells

Embryonic Stem cells (ESCs) and Induced Pluripotent Stem Cells (iPSCs) are moving ahead into clinical trials considering their significant role as a therapeutic agent. Clinical Trial- (NCT02057900) was ongoing to assess the safety and feasibility of transplantation of cardiac-committed progenitor cells derived from human embryonic stemcells,inpatients with severe heart failure undertaken by the Department of Cardiovascular Surgery, Paris, France. It is an open-label, an interventional study consisting of 10 participants where patients with is chemic heart failure are receiving an epicardial delivery of fibrin gel embedding human embryonic stem cell-derived CD15+ Isl-1+ progenitors. The primary focus is to understand if clinical trials show any evidence for new clinical/biological abnormalities, the occurrence of arrhythmias or development of a cardiac or an extracardiac tumour.

Cell therapies utilising iPSCs are being explored in a significant way.Geng Z et al., from Stem Cell Institute, Minnesota, USA have reported the generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age-related macularde generation. They have successfully validated a standardised, iPSC derivation and RPE differentiation process that will be useful for applications which require the cost-effective generation of RPE from multiple individuals such as therapies requiring patient-specific RPE derivations, population studies or drug testing.

Mesenchymal Stem Cells (MSCs)

Stem Cell therapies using MSCs have increased in a notable way. These have the biological characteristics of immune regulation, self-renewal, tissue repair and multidirectional differentiation. A recent clinical study being undertaken by The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China aims to understand the efficacy and safety of Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) in the treatment of Ocular corneal burn in humans which is one of the causes of vision loss in China. Preliminary results suggest that UC- MSCs can accelerate corneal repair and inhibit angiogenesis. It is a Placebo-Controlled, Randomised, Doubleblind, Interventional Trial consisting of 100 participants where the main focus is to understand the percent of corneal perforation.

Cerebral palsy refers to a neurological disorder caused by a non-progressive brain injury or malformation that occurs in early childhood. The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China aims to evaluate the safety and efficacy of UC-MSCs and compare the efficacy of UC-MSCs administered through the intravenous, intrathecal, and intranasal routes, in the treatment of cerebral palsy in children through clinical studies (NCT03414697). It will be an interventional, randomised study consisting of 44 participants focusing on gross motor function improvement.

Haematopoietic Stem Cells

Allogeneic haematopoietic stem cell transplantation has been successfully used for the treatment of haematopoietic malignancy. Tianjin Medical University Cancer Institute and Hospital have undertaken a clinical trial to evaluate the safety and efficacy of non-myeloablative haematopoietic stem cell transplantation in the treatment of pancreatic cancer (NCT03236883). It is an open-label, an interventional trial to understand the survival rate, response rate and report any cases of adverse events.

In addition, table 1 and table 2 give the brief information regarding the current clinical trials and granted patents on the stem cell-based therapy.

Revitalised Interest in Gene Therapy

In recent decades, the level of interest in gene therapy has been exceptional. The licensing of the first gene delivery products (Glybera®, uniQure), an intramuscularr AAV vector for the treatment of lipoprotein lipase deficiency which was approved by European Medical Agency in 2012 and StrimvelisTM (GlaxoSmithKline) for Adenosine deaminase deficiency (ADA-SCID), which was approved in 2016. More recently, the first CAR T cell based gene therapy product, Kymriah (tisagenlecleu cel-T and CTL019) developed by Novartis, was approved in August 2017 by the United States of Food and Drug Administration. In addition, table 1 and 2 shows the recent clinical approaches and granted patents on the gene therapy.

There has also been an increasein the number of industry sponsored collaborations with the academic sector, which may further magnify the gene therapy developmental pipeline. Although, with the clinical translation in mind, the more applied characteristics of gene delivery like optimising the protocols to manufacture the Good-Manufacturing Practice (GMP) grade based vector stocks and ensuring that these novel vectors are suitable for commercial manufacturing. Improved assurance in gene therapy for clinical exposure has also created strong competition in the biopharmaceutical sector for potentially lucrative disease indications like by using AAV vectors in the treatment of coagulation factor disorders Haemophilia A and B, where more than ten companies have declared or initiated trials.

The ability of gene therapy to cure human disorders is now an established realism, but for now, many diseases and pathophysiological processes potentially responsive to this exciting therapeutic tactic lie beyond the reach of present technology. Despite the vast developments in gene transfer technology, the ability to modify the cells for therapeutic advantage continues to limit the translation of pre-clinical replicas from bench to bed side and finally to standard clinical care. Such progresses are primarily dependent upon the sound basic and pre-clinical data coupled with iterative human clinical trials. Unwanted host-vector interactions i.e. immune responses against the vector and encoded transgene products, must also be better understood and avoided. Alternative approaches to prevent cell-mediated destruction of gene-corrected cells include modulation of the immune system, use of engineered vectors to evade capsid specific immune responses or transient immune suppression. The latter has been used successfully in clinical trials for Haemophilia B to limit hepatocellular toxicity and preserve expression of transgenic factor IX, especially when treatment was initiated early.

With an increasing number of therapeutic successes being reported and investment in gene therapy technologies advancing rapidly, factors related to the manufacture and commercialisation of products also need to be considered. Gene therapy also offers the potential of a single treatment resulting in a life-long cure which has led to the discussion on how such therapies will be valued and how companies might recover the extraordinary costs associated with a gene therapy product reaching the marketplace, as well as the investment made in those that are unsuccessful. Also, practicalities associated with the clinical manufacture of bespoke therapies, with CAR-T cells being significant, require consideration. Recent CAR-T cell therapies depend on the ex-vivo alteration and expansion of T cells harvested from individual patients and require specialised teams and proper facilities for manufacture, and the ability to meet increased demand for this ground breaking treatment is reaching capacity. To facilitate clinical tails of virus-mediated gene delivery, production must be scalable, reproducible and yield vector at the highest possible titers. To address these logistical and practical challenges, importance has been placed on developing procedures for the cryopreservation and transportation of gene-modified cells. This will allow the manipulation of patient cells to occur at centralised locations and may provide methodological consistency throughout the trials and has the potential to make gene delivery more accessible to patients worldwide.


In recent decades, the stem cell and gene therapies are an established reality and evolving at a rapid pace following the important foundations proved from predominantly early-phase trials, which have been basically ineffective in providing therapeutic benefit. These trials, however, have provided clear proof-ofconcept for stem cell and gene therapy demonstrated that the therapy is relatively safe, and highlighted important issues that must be considered to advance the field.

--Issue 31--

Author Bio

Ambikanandan Misra

Ambikanandan Misra is Professor of Pharmacy at Faculty of Pharmacy at The Maharaja Sayajirao University of Baroda. He has been associated with the field of pharmaceutical sciences for more than 39 years. 43 Ph.D. and 132 Master students have completed their dissertation under his guidance. He has 7 books, 41 book chapters and 165 peer-reviewed publications in reputed journals. He has filed 29 national and international patents out of which 9 have been granted so far.