Regeneration and mitigation: an opinionated take on NEJM highlights for March 2017

Gene therapy for sickle cell disease

Typical diseases targeted by gene therapy are those for which there is a defect that prevents the production of a functional protein needed for normal life; remediation is achieved by inserting functioning copies of the gene, and fortunately, it is usually the case that expression at a low level is sufficient to greatly improve outcomes. The situation is different in sickle cell where the defective hemoglobin is actually harmful, and where success of gene therapy requires not only production normal hemoglobin, but replacement of the defective hemoglobin. In an N-of-1 study, a French group harvested a large number of marrow stem cells from a patient with sickle cell, grew and modified these cells by inserting the corrected gene for hemoglobin, obliterated the remaining marrow of the patient with chemotherapy, and reinfused the modified cells in a variation of a standard autologous bone marrow transplant procedure commonly used in a blood cancers.  The patient is now symptom free. Beyond sickle cell disease, this showcases the growing ability for ex-vivo manipulation of autologous stem cells, with implications ranging from immuno-oncology to regenerative medicine. Gene Therapy in a Patient with Sickle Cell Disease (subscriber access)


The good and the ugly of regenerative medicine

In 2012 Yamanaka and Gurdon received the Nobel Prize for their work in showing how differentiated cells can be induced to become stem cells (iPSCs). From there forward, a central issue of regenerative medicine is how to induce appropriate redifferentiation into the desired tissue architecture, and this is the subject of a case study (with Yamanaka as co-author) in the context of macular degeneration. The investigators took a skin sample from a woman with macular degeneration, cultured fibroblasts from that sample, de-differentiated them into iPSCs, redifferentiated them into retinal cells, and cultured those cells ex-vivo into a sheet of tissue which was implanted surgically into one eye of the affected person who subsequently has had stable vision.  Therapeutic success is unclear at this stage, but the proof-of-concept of the approach has profound implications.  Meanwhile, on the US side of the ocean, a report on several patients with macular degeneration who paid to participate in a “stem cell trial” during which both their eyes were injected with “stem cells” isolated from liposuction of their abdomen. They experienced serious deterioration of their vision and are now blind. Most shocking is perhaps how on earth an IRB could sign off on such an experimental procedure involving not one, but both eyes?   Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration; Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD; Polar Extremes in the Clinical Use of Stem Cells (subscriber access)


PCSK9 inhibitors – after the price, the value

A flurry of data released at the American College of Cardiology meeting earlier this month was the subject of a number of papers simultaneously available on line at the NEJM. First among them, longer-term results from the FOURIER trial on evolocumab (Repatha, Amgen) which show that the treatment arm experienced 0.7 less major vascular events per 100 patient x year: by a back of the envelope calculation, this is two million USD per prevented event at the current list price of $14k/year of treatment – the consensus seems to be that it is too much: either the price has to come down, or the population should be restricted to those who have a sufficiently high risk that the effect will be larger.  For comparison Jardiance (a completely different drug for diabetes from Eli Lilly) reduces the major vascular event rate by 0.5 per 100 patient x year for a cost of $5k, a value twice as good as Repatha (and which does not even include microvascular benefits). Meanwhile, inclisiran (Alnylam and the Medicines Company) confirms its ability to profoundly decrease LDL under a twice a year dosing regimen, although the required studies to prove cardiovascular outcomes will not be completed for at least a few years. Finally a study on bococizumab (Pfizer, development now discontinued), another antibody directed against PCSK9 shows that not all antibodies are created equal. Unfortunately in some individuals, bococizumab raised antibodies against itself leading to rapid clearance and loss of effect in cholesterol reduction. A cautionary tale about the sometime random way in which biosimilars may behave in a therapeutic context. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease; Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol; Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients; Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab; PCSK9 Inhibition to Reduce Cardiovascular Events (free access)


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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