State of Research

Allele-iPSC News Translate: iPS clinical research encounters a problem. Doctors say “the problem is not caused by iPSCs”

Kobe City Medical Center General Hospital and Riken Research Institute announced and reported to the Japanese government that a patient who had received allogeneic iPSC-derived cells developed an “epi retinal membrane”, which they subsequently removed by operation. Dr. Masayo Takahashi at Riken says “the problem is caused by the transplantation procedure, but not by iPSCs. This will not affect future clinical research that uses iPSCs.”

The laws that govern regenerative medicine in Japan mandates that the deaths and hospitalizations that occur during treatment need to be reported to the government as “serious harmful effects”. This is the first such report involving iPSC clinical research.

The problem occurred to a man in his 70s, who is at the risk of blindness due to “wet age-related macular degeneration”. Last June, he received a transplantation of the solution containing allogeneic iPSC-derived retinal pigment epithelium (RPE) in his left eyes. Last October, the epi retinal membrane and swelling started to develop and the membrane was removed on January 15.

The possibility exists that the solution leaked from the needle hole during the transplantation, and the leaked cells might have formed the membrane. The transplanted cells inside the retina are stable and there has been no decline in his eyesight.

Dr. Takahashi says “although this event qualifies as a serious harmful event, the patient’s condition has not worsened and there has been no rejection of transplanted cells”. Dr. Yasuo Kurimoto, a surgeon who performed the operation, says “the procedure was the problem. We would like to improve the method, in order to make iPSC therapy a common treatment.”

The current clinical trial targets patients with wet age-related macular degeneration and is run by the Kobe City Hospital, Riken, Osaka-University Hospital, and Kyoto-University CiRA (Dr. Shinya Yamanaka). Between last March and October, five patients have received the transplantation.

Original News Credits: https://www.kobe-np.co.jp/news/iryou/201801/0010902012.shtml

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NIH Awards Allele Collaboration with Grant to Fund the Development of Cell-Based Therapy for Alzheimer’s Disease

The NIH’s National Institute on Aging has awarded Allele Biotechnology and Pharmaceuticals (“Allele”) a Phase 1 SBIR grant to develop a stem cell-based therapy for the treatment of Alzheimer’s disease. The award includes funds for consortium activity with researchers at The Scintillon Institute, whose expertise in neurodegeneration leverages Allele’s expertise in stem cell technology.

Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. Currently, there is no cure for this devastating disease. Patients with Alzheimer’s disease suffer from synaptic and neuronal loss, which is thought to be caused by the presence of a chemically “sticky” protein called amyloid beta (Aβ). The aggregates of Aβ may damage synaptic integrity and/or trigger immune cell activation, ultimately causing cell death.

Successful cell-replacement therapies would need to distribute cells to damaged areas in the brain and stimulate integration of new neurons into existing cellular networks. While the idea of replacing lost neurons sounds promising, even successfully transplanted neurons would face the same toxic environment that destroyed the original neurons.

Researchers at Allele and Scintillon propose a novel way to prevent further damage from Aβ to transplanted neural stem cells. They are collaborating to genetically modify human neural stem cells to express a small (58-amino acid) peptide derived from the protein called α1-takusan, which Scintillon researchers previously discovered to harbor a protective activity against Aβ-induced toxicity (1). The researchers will then transplant the cells expressing the α1-takusan fragment into transgenic mouse models to evaluate whether these cells can ameliorate or even rescue the neurological phenotypes related to Alzheimer’s disease.

The Allele-Scintillon team hopes that transplanting these cells will mitigate synaptic and neuronal damage from Aβ, ultimately leading to a novel cell-replacement therapy for Alzheimer’s disease. This is the second SBIR grant that Allele has received from the NIH on treating Alzheimer’s by combating Aβ toxicity; the first being the creation of nanoantibodies against Aβ, which has generated multiple single-domain antibodies now in early development.


(1) Nakanishi N, Ryan SD, Zhang X, Khan A, Holland T, Cho EG, Huang X, Liao FF, Xu H, Lipton SA, Tu S (2013) Synaptic protein alpha1-takusan mitigates amyloid-beta-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33:14170-14183. PMCID: PMC3756761

Prominent regulators of neurogenesis are also critical in maintaining eye health

A group of researchers at Scintillon Institute in San Diego, California and their collaborators identified important roles of myocyte enhancer factor 2 (MEF2) in the pathogenesis of stress-induced photoreceptor degeneration, a condition that is thought to contribute to eye diseases, such as retinitis pigmentosa and age-related macular degeneration, as described in two recent publications (1,2). MEF2 is an activity-dependent transcription factor which is expressed in various organs, such as the heart, lymphocytes and brain. Dr. Stuart Lipton’s group has continuously worked on MEF2 since 1993, when they first isolated MEF2C, one of four mammalian MEF2 isoforms, in the developing brain. These researchers made seminal discoveries that established the notion that MEF2 transcription factors are prominent regulators of neurogenesis and neuronal survival in the brain. More recently, their work on MEF2C mutant mice led to the recognition of the human disease called MEF2C haploinsufficiency syndrome, in which children with heterozygous loss-of-function MEF2C mutations suffer from severe neurological conditions, including autism spectrum disorders, developmental and intellectual disabilities and seizures.

Scientists at the Neural Center of the Scintillon Institute have been expanding on MEF2 research, most recently turning their eyes to eye diseases (pun intended). Retinal photoreceptor cells express two MEF2 isoforms: MEF2C and MEF2D, the latter apparently being the predominant form. In a recent study, the researchers examined mutant mice completely lacking MEF2C or MEF2D (MEF2C- or MEF2D- “null” mice). Interestingly, both mutant mice developed drastic retinal degenerations by postnatal day 30. They then took a candidate approach to identify the molecular pathways affected by the loss of MEF2D in MEF2D-null mice. Among the pathways they examined was the PGC1? pathway, which regulates mitochondrial biogenesis and thereby protects cells from degeneration. The Lipton group determined that transcription of PGC1? was indeed reduced in MEF2D-null mice. Yet by overexpressing PGC1? in the retina of MEF2D-null mice, the researchers found that the retinal degeneration could be rescued.

In another related study, they examined mice lacking one copy of MEF2D (MEF2D-heteretozygous or “het” mice). Unlike MEF2D-null mice, MEF2D-het mice did not show any retinal regeneration when they were raised under normal housing environment. The researchers then exposed MEF2D-het mice to a strong white fluorescent light for 2 hours. While this light exposure did not induce any retinal degeneration in the wild-type mice, it did cause significant retinal cell death in MEF2D-het mice. The light exposure massively produced reactive oxygen species (ROS), which appeared to be the toxic cause. When searching for affected downstream pathways, they found that the transcription factor NRF2, a regulator of the cellular antioxidant defense response, fails to be induced by light exposure in MEF2D mutant mice. The researchers attempted to reverse light-induced retinal cell death by treating the MEF2D-het mice with carnosic acid, a chemical they had previously identified as a potent antioxidant and NRF2 activator. Intriguingly, treatment of carnosic acid drastically ameliorated the amount of light-induced retinal cell death in the mutant mice.

Together, these studies from the Scintillon Institute identify MEF2 transcription factors as crucial molecules in maintaining eye health. Importantly, they have shown that MEF2 and its downstream pathways can be targeted by drugs such as carnosic acid. Incidentally, carnosic acid is a naturally occurring chemical that is contained in herbs such as rosemary and sage. So, there may be a health benefit in cooking chicken and turkey with rosemary!

1. Proc Natl Acad Sci USA 114, E4048

2. Inv Opthal Vis Sci 58, 3741

Tuesday, August 8th, 2017 State of Research No Comments

Ablynx Develops Nano Antibody for Treatment of Rare Clotting Disorder

Last week, Ablynx announced substantial progress in the development of the nano antibody drug caplicizumab to treat acquired thrombotic thrombocytopenic purpura (aTTP), a rare, but life-threatening autoimmune disease. The Belgian biopharmaceutical company has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for approval. If accepted, caplicizumab will not only be the first therapeutic specifically indicated for the treatment of aTTP, but also the first approved nano antibody drug on the market.

aTTP is characterized by the autoimmune impairment of ADAMTS13, an enzyme that normally cleaves multimeric von Willebrand factor (vWF) into its functional form. Without the function of ADAMTS13, multimeric vWF forms aggregates with platelets in the blood. Low free platelet count and excess clotting result in thrombotic complications and a significant risk of organ damage due to the blockages of blood flow to tissues.

The current standard of care for aTTP involves immunosuppression and daily plasma exchange transfusion, in which a patient’s plasma is replaced with donor plasma to remove platelet-vWF aggregates. Caplicizumab is an anti-vWF nano antibody that prevents the formation of aggregates by blocking the interaction of multimeric vWF complexes with platelets.

While dozens of monoclonal antibodies have been approved by the FDA for therapeutic use (with hundreds more undergoing clinical trials), caplicizumab is the first therapeutic nano antibody. Nano antibodies are single-domain antibody fragments that bear full antigen binding capacity like monoclonal antibodies, but have a smaller size and unique structure, giving them features of small-molecule drugs. Nano antibodies are more stable than conventional monoclonal antibodies, allowing for multiple administration routes, and can be humanized to lower toxicity and immunogenicity. Because they are encoded by single genes, nano antibodies are easier and more cost-effective than traditional antibodies to engineer and manufacture.

Currently, caplicizumab is undergoing Phase III clinical trials and a three-year follow-up study has been initiated to determine the long-term safety and efficacy of this drug. Ablynx aims to commercialize caplicizumab in North America and Europe upon the trial’s conclusion and approval of BLA filing in 2018.

With the obvious advantages of nano antibodies over conventional monoclonal antibodies as biological drugs, caplicizumab is likely only the first of many to come.

The NIH Awards Allele with Grant for the Development of a New Antibody Therapy for Treating Alzheimer’s Disease

SAN DIEGO–(BUSINESS WIRE)–

The National Institute on Aging of the NIH has awarded a grant to Allele Biotechnology and Pharmaceuticals (“Allele”) to develop a new antibody therapy for treating Alzheimer’s disease. Alzheimer’s disease is the most common cause of dementia, but there are currently no treatments to stop or reverse its progression.

Alongside academic collaborators, scientists at Allele have revealed a strong correlation between a previously uncharacterized target gene and Alzheimer’s disease. They discovered that expression of the gene reduces beta-amyloid production and tau phosphorylation, two components of plaque formation in Alzheimer’s disease. Furthermore, high levels of this protein in the brain can counteract loss of synapses and cognitive impairments in mice.

Allele will generate a panel of antibodies that recognize this protein with the goal of employing one of these antibodies as a therapeutic drug candidate. The antibodies’ unique size and shape allow them to pass the blood-brain barrier to reach crucial regions of the brain, and each antibody can be easily modified and engineered to heighten its therapeutic potential. Researchers at Allele hope that an antibody treatment will improve the function of its target protein in the brains of Alzheimer’s patients and ultimately reduce pathogenesis of the disease.

Recombinant antibodies represent one of the most important classes of biological therapeutics: 80% of the best selling drugs on the market are antibodies; immune checkpoint therapies and CAR-T cell therapies rely on antibodies. Continuously seeking unique antibodies against high value targets is a key focus of Allele, along with its induced pluripotent stem cell (iPSC) programs and iPSC-based drug screening projects. With the support of the new NIH grant, Allele will not only move closer to finding antibody drug candidates in fighting one of the most devastating diseases, but also generate long-needed research tools for other scientists to further study Alzheimer’s disease. For example, fusion of these antibodies to fluorescent proteins such as mNeonGreen can be used to image Alzheimer’s disease-related factors in cultured neurons, astrocytes, oligodendrocytes, or “minibrain”-like organoids derived from human iPSCs.

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