Using Skin Cells for create human Motor Neurons

A cocktail of two microRNAs and two transcription factors is enough to transform human skin cells directly into motor neurons, scientists report — an achievement of potentially considerable importance in understanding such motor neuron diseases as spinal muscular atrophy (SMA).

The study, “MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts,” appeared in the journal Cell Stem Cell.

Motor neurons are nerve cells of the central nervous system that transmit signals from the spinal cord to muscles to help them contract. Damage to these cells underlies several devastating and paralyzing diseases, from SMA to amyotrophic lateral sclerosis or ALS.

Scientists have struggled to grow human motor neurons in the lab for research purposes, which is one reason this work is so notable. Researchers at the Washington University School of Medicine in St. Louis, Missouri, were able to convert skin cells from healthy adults into motor neurons. Importantly, this process also didn’t require skin cells to change into stem cells before becoming motor nerve cells.

A technique that requires stem cell state often raises ethical issues, as is the case with pluripotent stem cells. These cells are similar to embryonic stem cells due to their ability to become any adult cell within the body. Moreover, cells that don’t need to undergo a stem cell state are the same age as their cells of origin — in this case, skin cells — and consequently, the same age as the patient whose skin was used to create the motor neuron cells.

“Going back through a pluripotent stem cell phase is a bit like demolishing a house and building a new one from the ground up,” Andrew S. Yoo, the study’s lead author and an assistant professor of developmental biology at Washington University, said in a press release. “What we’re doing is more like renovation. We change the interior but leave the original structure, which retains the characteristics of the aging adult neurons that we want to study.”

The science behind converting skin cells into motor neurons is linked to two small RNA molecules, called microRNAs, which are particularly rich in the brain. Previous research by Yoo and colleagues, while at Stanford University, showed that microRNA-9 and microRNA-124 were important in remodeling the genome so as to induce a neuronal state in cells.

In the current study, Yoo’s team further investigated the role of these microRNAs and how they help convert skin cells into motor neurons. It found that both microRNAs assist cells in holding at a stage where they are ready to convert to neurons. But they were inactive and need more help. After extensive research, researchers identified two transcription factors — ISL1 and LHX3 — were the missing link. Once added to the mix, skin cells turned into spinal cord motor neurons in about 30 days.

The four factors — microRNA-9, microRNA-124, ISL1 and LHX3 — help cells shed their skin cell “genetic identity” and embrace instructions that lead them to becoming motor nerve cells, scientists said.

The converted motor neurons showed a similar genetic profile — in terms of gene activation and how they work — to mouse motor neurons. How well their genetic profile compares to human motor neurons is still a question, because these cells are very difficult to obtain from living adults. Future studies with neuron samples from deceased patients will let researchers determine how well their converted motor neurons match natural human motor neurons.


“Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons,” Yoo concluded. “In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition.”

Text from: https://smanewstoday.com/2017/09/12/sam-research-may-get-boost-from-study-using-skin-cells-to-create-human-motor-neurons/

In the World has approved a new Drug Treatment for SMA!!!!!!!

Today, unusual day! In the World has approved a new Drug Treatment for SMA!!!!!!!

Today, the FDA announced that it has approved Spinraza (nusinersen) to treat spinal muscular atrophy, making it the first-ever FDA-approved therapy for SMA.

We are thrilled to see our community’s efforts culminate in the approval of Spinraza: not only the first-ever approved treatment for this disease, but also one that addresses the underlying genetic cause of SMA. This has been a story of all groups—families, researchers, companies and the FDA—working together as one community to reach this amazing milestone.

We are especially pleased that the sophisticated and rigorous clinical development plan that Biogen and Ionis chose to implement has resulted in a broad label that will now give so many patients access.

The approval from the FDA for all SMA—pediatric and adult—is the broadest possible label, with no restrictions—and this matches our core value at Cure SMA of being one united community for all ages and all types of SMA.

“Biogen is committed to continuing to work together with the SMA community as we embark on a future where there is now a treatment available for this devastating disease,” said George A. Scangos, PhD, chief executive officer at Biogen. “The teams at Biogen and Ionis are grateful for the support we have received and we join Cure SMA and SMA families in celebrating this critical milestone for the community.”

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”

An Historic Moment for the SMA Community

This is an historic moment that our community has been working toward for decades. We extend our deepest gratitude to all our chapters, families, supporters, donors, and partners who have contributed to this milestone.
“This is a landmark day for the SMA community with the first approved drug for the disease. Cure SMA and our entire community have worked together tirelessly for more than thirty years to make this happen. It is important for all of us to stop and celebrate this shared accomplishment that will change and improve the lives of SMA patients,” said Jill Jarecki, PhD, Cure SMA’s Chief Scientific Officer.
Thank You

From 2003 to 2006, Cure SMA provided the very first research funding needed to begin investigation into this therapeutic approach. We thank Drs. Ravindra Singh and Elliot Androphy of the University of Massachusetts Medical School for their work funded by Cure SMA in originally identifying the ISSN1 gene sequence, which is the sequence targeted by Spinraza. We acknowledge Dr. Adrian Krainer and his colleagues at Cold Spring Harbor Laboratory for generating critical intellectual property. All this work was then licensed to Ionis Pharmaceuticals to create the antisense therapy Spinraza. We especially appreciate the team at Ionis for their central role in the rapid advancement of Spinraza.

We are particularly thankful to our partners at Biogen. Together with Ionis, Biogen worked to develop and implement a comprehensive clinical testing program that would provide both the quickest route to approval and the high quality data necessary to support a broad label and access. We thank the families who made many sacrifices to participate in these clinical trials, including the placebo-control groups which were so critical to prove the effectiveness of Spinraza for the whole community.
Finally, we want to recognize the FDA for their partnership with us throughout this process. The FDA understood the critical urgency within our community and acted incredibly quickly to review the robust data submitted in the New Drug Application.
“This first approved treatment provides the greatest hope, and reaffirms the commitment made by the entire community, to create a world without spinal muscular atrophy and rid the world of the suffering wrought by this terrible disease,” said Richard Rubenstein, Chair of the Cure SMA Board of Directors. “It is gratifying to see all of the efforts made by so many people for so many years realized with this breakthrough.”
More About Spinraza

SMA is caused by a mutation in the survival motor neuron gene 1 (SMN1). In a healthy person, this gene produces a protein—called survival motor neuron protein or SMN protein—that is critical to the function of the nerves that control our muscles. Without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness.
All individuals affected by SMA have at least one copy of survival motor neuron gene 2 (SMN2), often referred to as the SMA "backup gene." Due to a splicing error, most of the SMN protein made by SMN2 is missing an important piece, called exon 7. Antisense drugs are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA), so they can be used to fix splicing errors in genes such as SMN2. Spinraza is antisense oligonucleotide that targets SMN2, causing it to make more complete SMN protein.
Spinraza was first known as IONIS-SMNRx, then nusinersen.

Timeline of Events

2003 - 2006: Cure SMA makes $500,000 in seed grants to fund the therapeutic approach that led to Spinraza.

July 2010: Ionis (then known as Isis Pharmaceuticals) licenses the intellectual property to begin development of Spinraza.

December 2011: Ionis initiates a Phase 1 clinical trial of Spinraza.

January 2012: Biogen and Ionis enter into a partnership agreement to continue developing Spinraza.

April 2013: Ionis begins testing Spinraza in Phase 2 clinical trials.

August 2014: Ionis and Biogen launch ENDEAR, a Phase 3 clinical trial testing Spinraza in infants with SMA type I.

November 2014: Ionis and Biogen launch CHERISH, a Phase 3 clinical trial testing Spinraza in children with SMA type II.

March 2015: Biogen and Ionis launch NURTURE, a Phase 2 clinical trial testing Spinraza in infants genetically diagnosed with SMA but not yet showing symptoms.

August 12, 2016: Biogen and Ionis announce their intention to initiate regulatory filings for Spinraza, after the drug meets its primary endpoint in an interim analysis of ENDEAR.

September 26, 2016: Biogen and Ionis announce that they have completed their rolling NDA submission to the FDA and EMA.

October 28, 2016: Biogen and Ionis announce that the FDA has accepted their New Drug Application with priority review.

November 7, 2016: Biogen and Ionis announce that SPINRAZA also met its primary endpoint in an interim analysis of CHERISH.

December 23, 2016. The FDA approves Spinraza for SMA.

Text from; http://www.curesma.org/news/spinraza-approved.html