Targeted Delivery of Gene and Cell Therapies

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Gene and cell therapies represent the next-generation treatments for a wide range of diseases, but one challenge in the development of these therapeutics is the controlled delivery to the targeted site to maximize expression or engraftment while limiting systemic exposure.

Gene and cell therapies represent the next-generation treatments and potential cures for a wide range of diseases from cancer to cardiovascular and neurologic disorders. Cellular therapeutics have the potential to engraft and replace diseased tissue and to recruit endogenous repair mechanisms to the site of injury. Gene therapies allow for the introduction of genetic material to the target cells for the treatment of a number of diseases. One of the primary challenges in the development of these therapeutics is the controlled delivery to the targeted site to maximize expression or engraftment while limiting systemic exposure.

Cardiovascular therapeutics
In cardiovascular research and regenerative medicine, several targeted delivery methodologies (such as epicardial injection, endocardial injection, intra-coronary infusion, and retrograde perfusion) are used to deliver a therapeutic to the heart. Each of these delivery methods may result in differing levels of gene expression or cell engraftment depending upon the therapeutic, the carrier, and the protocol used for delivery of the therapeutic. During preclinical development, it is important to evaluate the optimal methodology for delivery of the therapeutic prior to assessment of safety, biodistribution, and efficacy. Determination of the optimal methodology is typically accomplished through a multi-group study and comparison of either cell engraftment or gene transfection and expression using the different routes of administration in an appropriate animal model.

Other factors to consider when choosing a cardiac delivery device include the target patient population and level of disease to be treated. For example, the use of an endocardial injection catheter may not be appropriate for a patient population with advanced heart failure and thinning of the ventricular wall. Intra-coronary delivery may not be appropriate in patients with advanced coronary artery disease of multiple occlusions as this method will affect distribution and may pose a safety risk.

Neurologic therapeutics
Likewise, the delivery method chosen for a neurologic disease is dependent on the type of disease, the type of therapeutic, and the desired distribution within the central nervous system (CNS). Many gene therapies are administered as an intrathecal or intracerebral ventricular injection into the cerebral spinal fluid to maximize distribution to the brain and spinal cord. For genetic diseases such as giant axonal neuropathy disease, Batten disease, and spinal muscular atrophy (SMA), the cellular targets are throughout the CNS. Evaluation of distribution of the cellular therapy can be accomplished during the preclinical program through assessment of CSF levels of the therapeutic, analysis of tissue samples for expression of the gene, and analysis of tissue samples for the presence of the viral vector, if used.

Over the past decade cellular therapies have shown great promise in the treatment of neurodegenerative disease, such as Parkinson’s Disease, stroke, and spinal cord injury. Unlike gene therapies, cellular therapies are typically administered at a specific location within the CNS to treat the disease or injury. This administration is typically accomplished through stereotaxic injection to a specific location with in the brain or spinal cord. This route of administration limits the distribution of the therapeutic in an attempt to ensure engraftment in the tissue.

Gene therapy has the potential to target cancer cells or activate endogenous mechanism to combat the disease while sparing healthy tissues. A common method of delivery is by intravenous injection or infusion of the gene therapy. This method subjects the entire patient to the vector with the intent of transfecting a target cell population to combat the cancer.

Targeted delivery of the gene therapy is also being used in the treatment of brain, prostate, colorectal, pancreatic, hepatic cancers, and mesothelioma. Such targeted delivery limits the systemic exposure and increases the transfection potential of the target cell population.


Preclinical study considerations
Safety and biodistribution are important when designing a preclinical program to assess a gene or cell therapy, but there also other factors that need to be considered, such as the potential immune response to the gene therapy, and for a cell therapy, the persistence and tumorigenicity. If using a specific delivery device, the safety of the device in combination with the therapeutic should be assessed.

In addition, the investigator should determine if the safety program should be conducted in a disease model versus healthy animals. For example, a therapeutic may have different transfection or engraftment profiles in a diseased animal compared with a healthy animal. In some cases, healthy and diseased animals may respond differently to the use of the injection device.

The preclinical program for a gene therapy should include multiple necropsy time points that cover the time of peak expression, interim time points that demonstrate clearance of the a viral vector, if used, and a terminal time point that has been demonstrated to represent clearance and long term safety. On the other hand, for a cell therapy, the preclinical program should include multiple necropsy time points that demonstrate acute and chronic safety of the therapeutic, persistence of the cells (how long are the cells present in the tissues), distribution of the cells form the site of administration, and the potential for formation of tumors. Each of these time points is dependent upon the individual therapeutic.

Safety, biodistribution, and efficacy must be ensured before the gene or cell therapeutic progresses to clinical trials. Investigators should also meet with their regulator body to solicit input prior to starting the preclinical and clinical programs. 

About the AuthorMark D. Johnson is senior study director and senior director of surgery at MPI Research.