From Bench to Bedside: Review of Gene and Cell-Based Therapies and the Slow Advancement into Phase 3 Clinical Trials, with a Focus on Aastrom’s Ixmyelocel-T

Abstract

There is a large body of preclinical research demonstrating the efficacy of gene and cellular therapy for the potential treatment of severe (limb-threatening) peripheral arterial disease (PAD), including evidence for growth and transcription factors, monocytes, and mesenchymal stem cells. While preclinical research has advanced into early phase clinical trials in patients, few late-phase clinical trials have been conducted. The reasons for the slow progression of these therapies from bench to bedside are as complicated as the fields of gene and cellular therapies. The variety of tissue sources of stem cells (embryonic, adult bone marrow, umbilical cord, placenta, adipose tissue, etc.); autologous versus allogeneic donation; types of cells (hematopoietic, mesenchymal stromal, progenitor, and mixed populations); confusion and stigmatism by the public and patients regarding gene, protein, and stem cell therapy; scaling of manufacturing; and the changing regulatory environment all contribute to the small number of late phase (Phase 3) clinical trials and the lack of Food and Drug Administration (FDA) approvals. This review article provides an overview of the progression of research from gene therapy to the cellular therapy field as it applies to peripheral arterial disease, as well as the position of Aastrom’s cellular therapy, ixmyelocel-T, within this field.

Regulating myogenic differentiation of mesenchymal stem cells using thermosensitive hydrogels

“…These include bone marrow and peripheral blood mononuclear cells [11][12][13][14][15][16][17], mesenchymal stem cells (MSCs) [18][19][20][21][22], cell lines selected based on the presence of specific markers [15,[23][24][25], adipose tissue-derived cells [26][27][28][29], and induced pluripotent stem cells-derived cells [30,31]. Each of these cell types has shown promise for the treatment of CLI in mechanistic and preclinical studies.…”

Gene Therapy for Peripheral Arterial Disease and Nursing Implications: Clinical Experience on the use of Sendai Viral Vector

“…Thefirst-in-man clinical trial of therapeutic angiogenesis was conducted using naked plasmid VEGF165 in 1994 [14]. Since then, the proof of concept in preclinical studies has shown promising results, yet few late-phase clinical trials have been performed [15].…”

Adult Stem Cells and Cardiac Regeneration

“…Sources of donor stem cells, autologous versus allogeneic cell sources, types or lineages of cells, remain critically important considerations [43]. It has been noted that public perception of stem cell therapy as well as manufacturing challenges and the regulatory environment all contribute to the small number of late phase (Phase 3) clinical trials undertaken to date and the lack of Food and Drug Administration (FDA) approvals in the US [43]. Nevertheless, there is progress being made and some data with mixed cell populations are interesting.…”

“…Nevertheless, there is progress being made and some data with mixed cell populations are interesting. For example, Aastrom Biosciences has developed a proprietary cellprocessing technology, ixmyelocel-T, a patient-specific multicellular therapy based on expansion of cells from a small sample of a patient's own bone marrow [43,44]. Ixmyelocel-T uses current good manufacturing practices to expand the MSCs and macrophages.…”

“…Clinical trial data collected to date support the potential for ixmyelocel-T as an efficacious and safe treatment for ischemic cardiovascular indications, including critical limb ischemia and a severe form of heart failure, dilated cardiomyopathy (DCM). The CLI clinical program has completed phase 2 and agreement has been reached for an FDA-approved phase 3 study (REVIVE) through the Special Protocol Assessment process [43][44][45][46].…”