Catálogo de publicaciones - libros

This chapter outlined the authors’ current perspective on the complexities of general product testing requirements and design characteristics for preclinical studies involved in investigational use of cellular products for cardiac repair. The IND process is intended to balance the potential benefit of novel therapies to society with the need to generate data for prudent product development, to increase scientific knowledge, to protect subject safety, and to benefit the public health. This chapter represents an introduction to the regulation of these cellular products and investigator/sponsors are encouraged to contact FDA CBER OCTGT for more specific information on the conduct of clinical trials.

For continued clinical gains in the practice of radiotherapy, management of breathing motion is essential. The problem of organ motion in radiotherapy is complex; thus, interventions to reduce organ-motion-related uncertainties require effort, expertise, and collaboration from many disciplines. The application of image-guidance techniques, i.e., imageguided radiotherapy, will play an increasing important role in developing new and improved delivery techniques, i.e., adaptive radiotherapy. With some anecdotal clinical evidence and many potentially beneficial but unproven technologies under development and on the horizon, it is essential to place equal emphasis on the planning and implementation of prospective clinical trials.

As the efforts at translating cellular therapy to bedside continue, some of the current controversies may be resolved as answers to some questions become evident. Noninvasive imaging with PET should help to demonstrate changes in regional blood flow and metabolism that may ultimately account for the observed improvement in LV function and/or remodeling. PET imaging may be able to provide mechanistic insights to understand the causes of success and failure of cell therapy, and ultimately help improve the design of this promising, novel form of therapy for this difficult group of patients

Early results of endoventricular cell transplantation demonstrate that this approach is feasible and safe in the models tested. The procedure is likely to have application in a majority of patients with previous myocardial infarction and congestive heart failure as the risks associated with a minimally invasive endoventricular injection are potentially lower than those linked with direct epicardial injection. The use of 3-D guidance appears to be key in accurately targeting areas that need to be treated, and catheters and cell preparations to be used in humans should be pretested for biocompatibility and safety. While catheter injection of cells is a relatively new innovation, the ability to access the heart without having to perform a median sternotomy will certainly encourage further evaluation of its potential for delivering many therapeutic biologic agents.

Epicardial transplantation of skeletal myoblasts in conjunction with a CABG or LVAD procedure is feasible and safe, and it does not appear that 116 Edward B. Diethrich cell transplantation poses a substantial risk of life-threatening arrhythmia in this small evaluation. Further study of the efficacy of myoblast transplantation is warranted, and we are now involved in investigations of catheterbased delivery systems and imaging protocols that support percutaneous skeletal myoblast transplantation (as described in “Percutaneous Myoblast Transplantation”, chapter 14 of this text).

In this chapter, we describe an method for the formation of contractile 3-D cardiac muscle, which we have termed cardioids. Cardioids are formed from the spontaneous delamination of a confluent monolayer of primary cardiac myocytes. One of the most attractive features of the cardioid model is that isolated cardiac cells self-organize to form 3-D cardiac muscle. This eliminates the need for synthetic scaffolding material in the contractile region of cardioids and allows cardioids to exhibit uninhibited contractions. Cardioids have been shown to exhibit several physiologically relevant metrics of function. Cardioids can be electrically stimulated to generate active force and can be electrically paced at frequencies of 1–7 Hz. In addition, cardioids are responsive to calcium and various cardio-active drugs. The cardioid model has several potential applications in basic research and may provide viable cardiac tissue for clinical applications.

As the efforts at translating cellular therapy to bedside continue, some of the current controversies may be resolved as answers to some questions become evident. Noninvasive imaging with PET should help to demonstrate changes in regional blood flow and metabolism that may ultimately account for the observed improvement in LV function and/or remodeling. PET imaging may be able to provide mechanistic insights to understand the causes of success and failure of cell therapy, and ultimately help improve the design of this promising, novel form of therapy for this difficult group of patients

The heart is a muscular pump that generates force in order to do work and pump volume. The major determinants of its ability to perform these functions are its size, mass, innate strength or contractility, preload and afterload. While all of these parameters should be kept in mind when assessing cardiac function, assessment of most pathologies and therapies rely on measuring contractility. Despite major advances in our understanding of cardiac function over the past 50 years, a simple, easily applied and accurate measure of contractility still eludes us. Easily applied measures lack sensitivity and accuracy while complex measures are cumbersome and difficult to apply. These principles must be kept in full view in order to avoid errors in assessing cardiac function.

Treatment of damaged myocardium after myocardial infarction by cell transplantation is becoming an increasingly promising therapeutic approach. Ideally, the donor cells should be amplified efficiently in culture and would lead to regeneration of infarcted myocardial tissue, including cardiogenic differentiation with local angiogenesis. Two of the most widely used cell types for cardiac repair today are skeletal muscle-derived progenitors, or myoblasts, and bone marrow-derived progenitors. Both cell types share advantages over other cells used for cardiac repair (or at least for limiting infarcts) in that they are readily available, autologous, exhibit a high proliferative potential and share a low potential for tumor genesis.

However, the transplantation of autologous cells to repair the heart also has serious drawbacks. It is labor intensive since isolation and cell proliferation has to be done for each patient. This procedure also delays the treatment. The ‘ideal’ cell to treat the heart should be transplantable without delay to any patient without a sustained immunosupression. Such ideal cells may be obtained one day by the genetic engineering of embryonic stem cells.

Through cellular therapies, the concept of “growing” heart muscle and vascular tissue and manipulating the myocardial cellular environment may revolutionize the approach to treating heart disease.

This chapter outlined the authors’ current perspective on the complexities of general product testing requirements and design characteristics for preclinical studies involved in investigational use of cellular products for cardiac repair. The IND process is intended to balance the potential benefit of novel therapies to society with the need to generate data for prudent product development, to increase scientific knowledge, to protect subject safety, and to benefit the public health. This chapter represents an introduction to the regulation of these cellular products and investigator/sponsors are encouraged to contact FDA CBER OCTGT for more specific information on the conduct of clinical trials.