European Medicines Agency (EMA; www.ema.europa.eu/ema/) has issued a guideline defining scientific principles and providing guidance for developing and evaluating medicinal products containing genetically modified cells intended for use in humans, and presented it for marketing authorization. The quality section addresses requirements for the genetic modification of the target cell population and for the transduced cell product resulting from the manufacturing process. The nonclinical section addresses nonclinical studies required, with the goal of maximizing the information obtained on dose selection for the clinical trials, to support the route of administration and the application schedule. The clinical section addresses the requirements for studying as far as possible pharmacological properties of the cells itself and the transgene.
Osiris Therapeutics (www.osiris.com) received market authorization from Health Canada to market its stem cell therapy Prochymal (remestemcel/L) for acute graft/versus/host disease (GvHD) in children. The decision marks the world's first regulatory approval of a manufactured stem cell product, and the first therapy approved for GvHD. Prochymal was authorized under Health Canada's Notice of Compliance with conditions pathway, which provides access to therapeutic products that address unmet medical conditions and have demonstrated a favorable risk–benefit profile in clinical trials. In patients with severe refractory acute GvHD, Prochymal demonstrated clinically meaningful response 28 days after initiation of therapy in 61–64% of patients treated. Prochymal treatment also yielded statistically significant improvement in survival compared with a historical control population of pediatric patients with refractory GvHD.
Four children with aromatic l/amino acid decarboxylase (AADC) deficiency showed improved motor functioning in a phase 1 clinical trial after the AADC gene was injected into their brains with an adeno/associated virus (AAV) type 2 vector, according to study results published in Science Translational Medicine. Researchers led by Wuh/Liang Hwu of National Taiwan University Hospital and National Taiwan University College of Medicine (Taipei, Taiwan) injected 1.6×1011 vector genome copies of AAV2/hAADC into the putamen of one boy and three girls, 4 to 6 years of age. Although at first they exhibited dyskinesias, these resolved after a few months: One child could stand after 16 months, and the other three were able to sit upright with support. Several other symptoms improved as well, including mood and oculogyric crises.
Gene transfer of engineered T cells with retroviral vectors holds promise for long/term delivery of protein/based therapeutics to treat cancer and HIV infection, according to researchers from the University of Pennsylvania's Perelman School of Medicine (Philadelphia, PA). In results published in Science Translational Medicine, the researchers found that 43 HIV/infected patients treated with gammaretroviral vector/engineered T cells showed no sign of adverse events for 11 years after initial treatment. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). The results mark the first time stable engraftment of transduced T cells has been demonstrated in such a time frame.
Researchers at the Spanish National Cancer Research Center (CNIO) published proof/of/principle results showing a role for telomerase reverse transcriptase (TERT) in demonstrating the feasibility of gene therapy in delaying physiological aging and extending longevity in normal mice. The CNIO team, led by director María A. Blasco, reported in EMBO Molecular Medicine that 1/ and 2/year/old mice treated with an adeno/associated virus (AAV) of wide tropism and expressing mouse TERT showed numerous beneficial effects on insulin sensitivity, osteoporosis, neuromuscular coordination, and several molecular biomarkers of aging. Telomerase/treated mice showed median life span increases of 24% for 1/year/olds and 13% for 2/year/olds. Importantly, telomerase/treated mice did not develop more cancer than control mice, suggesting tumorigenic activity is severely decreased when expressed in adult or old organisms using AAV vectors.
