Category Archives: Transhuman News

This study describes the findings from the targeted delivery of gene therapy to midbrain to treat a rare deadly neurodevelopmental disorder in children with a neurogenetic disease, aromatic L-amino acid decarboxylase (AADC) deficiency characterized by deficient synthesis of dopamine and serotonin.

The directed gene therapy in seven children ages 4 to 9 who were infused with the viral vector resulted in dramatic improvement of symptoms, motor function and quality of life. Six children were treated at UCSF Benioff Childrens Hospital in San Francisco and one at Ohio State Wexner Medical Center. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future, Bankiewicz said.

Researchers believe this same method of gene therapy can be used to treat other genetic disorders as well as common neurodegenerative diseases, such as Parkinsons and Alzheimers disease. Clinical trials are underway to test this procedure in others living with debilitating and incurable neurological conditions.

The directed gene therapy, in these patients, resulted in dramatic improvement of symptoms, motor function and quality of life. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future.

The findings described in this study are the culmination of decades of work by teams from multiple academic institutions, including University of California San Francisco, Washington University in St. Louis, Medical Neurogenetics Laboratory in Atlanta, St. Louis Childrens Hospital and Nationwide Childrens Hospital in Columbus, Ohio.

This work provides a framework for the treatment of other human nervous system genetic diseases. Its our hope that this will be first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner, Bankiewicz said.

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Innovative gene therapy 'reprograms' cells to reverse neurological deficiencies - Wexner Medical Center - The Ohio State University

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Friday, July 16, 2021

Results provide hope for children with aromatic L-amino acid decarboxylase deficiency.

A new study published in Nature Communications suggests that gene therapy delivered into the brain may be safe and effective in treating aromatic L-amino acid decarboxylase (AADC) deficiency. AADC deficiency is a rare neurological disorder that develops in infancy and leads to near absent levels of certain brain chemicals, serotonin and dopamine, that are critical for movement, behavior, and sleep. Children with the disorder have severe developmental, mood dysfunction including irritability, and motor disabilities including problems with talking and walking as well as sleep disturbances. Worldwide there have been approximately 135 cases of this disease reported.

In the study, led by Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at Ohio State College of Medicine in Columbus, and his colleagues, seven children received infusions of the DDC gene that was packaged in an adenovirus for delivery into brain cells. The DDC gene is incorporated into the cells DNA and provides instructions for the cell to make AADC, the enzyme that is necessary to produce serotonin and dopamine. The research team used magnetic resonance imaging to guide the accurate placement of the gene therapy into two specific areas of the midbrain.

Positron emission tomography (PET) scans performed three and 24 months after the surgery revealed that the gene therapy led to the production of dopamine in the deep brain structures involved in motor control. In addition, levels of a dopamine metabolite significantly increased in the spinal fluid.

The therapy resulted in clinical improvement of symptoms. Oculogyric crises, abnormal upward movements of the eyeballs, often with involuntary movements of the head, neck and body, that can last for hours and are a hallmark of the disease, completely went away in 6 of 7 participants. In some of the children, improvement was seen as early as nine days after treatment. One participant continued to experience oculogyric crises, but they were less frequent and severe.

All of the children exhibited improvements in movement and motor function. Following the surgery, parents of a majority of participants reported their children were sleeping better and mood disturbances, including irritability, had improved. Progress was also observed in feeding behavior, the ability to sit independently, and in speaking. Two of the children were able to walk with support within 18 months after receiving the gene therapy.

The gene therapy was well tolerated by all participants and no adverse side effects were reported. At three to four weeks following surgery, all participants exhibited irritability, sleep problems, and involuntary movements, but those effects were temporary. One of the children died unexpectedly seven months after the surgery. The cause of death was unknown but assessed to be due to the underlying primary disease.

Jill Morris, Ph.D., program director, NIHs National Institute of Neurological Disorders and Stroke (NINDS). To arrange an interview, please contact nindspressteam@ninds.nih.gov

Pearson TS et al., Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons, Nature Communications, July 12, 2021. https://doi.org/10.1038/s41467-021-24524-8

This study was supported by NINDS (R01NS094292, NS073514-01).

The NINDS NINDS is the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Link:
funded study finds gene therapy may restore missing enzyme in rare disease - National Institutes of Health

What happened

Companies associated with gene-editing are near the end of their second poor week in a row on Wall Street. For the week, shares of CRISPR Therapeutics (NASDAQ:CRSP) were down by 12% as of Thursday's market close. Editas Medicine (NASDAQ:EDIT) was off by about 14% over those four days, and Beam Therapeutics (NASDAQ:BEAM) had lost 15%.

Those downward moves came on the heels of a huge June run-up after Intellia Therapeutics (NASDAQ:NTLA) -- another gene-editing company -- announced that its approach had successfully reversed a genetic disease in human patients. In a clinical trial first, researchers injected a CRISPR treatment into patients that effectively inactivated the body's production of a mutated (and eventually toxic) form of a protein by altering the patients' DNA. Intellia and its partner Regeneron will now navigate the standard regulatory review process. Intellia CEO John Leonard has said he hopes the therapy becomes available to patients "very, very soon." However, marketability could still be years away. Meanwhile, Wall Street's recent surge of excitement about CRISPR therapies has worn off.

BEAM data by YCharts

The drops are notable as investors initially saw this breakthrough result as a positive for all gene-editing stocks. CRISPR Therapeutics, Editas, and Intellia are all taking similar approaches to editing genes -- using the CRISPR-Cas9 enzyme, which functions like a scissors. Beam Therapeutics, on the other hand, uses base-editing, an approach that alters DNA more like a pencil and eraser. Nearly three weeks removed from Intellia's announcement, the market has clearly decided its breakthrough is much more company-specific.

Image source: Getty Images.

It appears gene-editing investors who don't hold Intellia will have to wait for their own companies' catalysts to see big gains. Of these three, CRISPR Therapeutics is the one whose lead candidate is furthest along in clinical trials. CRISPR and its partner, Vertex Pharmaceuticals, have dosed more than 40 patients in a trial studying CTX001 in patients with sickle cell and beta-thalassemia. All patients at least three months removed from the procedure have shown a consistent and positive response to CTX001. Every previously transfusion-dependent patient in the trial has become transfusion-free since receiving the one-time treatment.

CTX001 is currently in a phase 1/2 study, and CRISPR Therapeutics hasn't offered any estimates about when it anticipates that it could be commercially available. But it recently signed an agreement with a smaller startup, Capsida Biotherapeutics, to develop an in vivo therapy for two diseases -- amyotrophic lateral sclerosis (ALS) and Friedreich's ataxia.

Editas has both in vivo and ex vivo (gene-editing done outside the body) candidates in early-stage clinical trials. Its in vivo candidate, EDIT-101, is a treatment for the most common form of childhood blindness. For this program, management has a meeting scheduled with the independent data monitoring committee this summer, and plans to share clinical data by the end of the year.

The company's also developing an ex vivo treatment for sickle cell disease that takes a slightly different approach than the one being used by other gene-editing companies. Editas is using the Cas12a enzyme instead of the more commonly used Cas9. The Cas12a approach has shown better editing efficiency in some studies and only requires one RNA molecule for editing as opposed to Cas9, which requires two.

For now, Beam Therapeutics is furthest back on the research and development path. Its programs are in preclinical stages. Its most advanced candidate also targets sickle cell disease and beta-thalassemia.

Investors' excitement about Beam has been less about its individual treatments and more about the gene-editing technology the company is using. Its base-editing approach could offer a more precise and predictable tool to modify DNA for treating diseases. The company hopes that will allow it to effectively leapfrog its rivals in the next few years. Management has predicted it will file with the FDA for an investigational new drug (IND) designation for its lead candidate later this year. Receiving that designation will give it the green light to test the treatment in humans trials. It also plans to move two more programs into the IND-enabling stage.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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Why CRISPR Therapeutics, Editas Medicine, and Beam Therapeutics Dropped This Week - The Motley Fool

A Charlotte baby became the first at UNC Medical Center in Chapel Hill, N.C. to receive a breakthrough gene therapy treatment for spinal muscular atrophy (SMA), after his condition was discovered through the Early Check newborn screening pilot study.

It was a pregnancy that went relatively smooth. No red flags. No urgent ultrasounds. But, for this one family of Charlotte, N.C., that sense of apprehension was always lurking.

It was like I was waiting for the other shoe to drop. After all that we went through with our first child, once we had our son, it seemed too easy to feel like everything was normal, said the mom, who wishes to be anonymous.

Their first child was born with health issues that went undetected during the moms pregnancy, and it was a surprise at birth.

So, my pregnancy with my second child, my son, was super simple aside from the fact that I would consider myself slightly traumatized from what happened with my oldest. Other than that, the pregnancy was easy and enjoyable, she said.

Their son was born February 25th, 2021, perfect in every way, at least on the outside. Around this time the parents received an envelope in the mail informing them about Early Check, a pilot study focused on screening newborns for rare health conditions, and how parents could sign their babies up prenatally or postnatally.

After speaking with our pediatrician, and realizing how enrolling our son in this study could make a difference, we decided to register, said the mom, whose intuition also played a role in her familys decision. Little did she know her gut decision would allow her child to live a more normal life.

The pilot study is in collaboration between RTI International, North Carolina State Laboratory of Public Health (NCSLPH), and three major universities the University of North Carolina at Chapel Hill, Duke University and Wake Forest University. Among many other rare conditions, Early Check launched screening for spinal muscular atrophy (SMA) in October 2018 throughout the spring of 2021.

With Early Check, we started including SMA because it wasnt a part of the general newborn screening for the state, so it was a pilot to see how it could work and to see if we could identify this condition in newborns, said Cynthia Powell, MD, pediatric geneticist, UNC site principal investigator for Early Check.

Results No Parent Wants to Hear

When their baby was three-weeks-old, the parents registered their son to be a part of the study. Four days later, they received a phone call.

It was one of those really nice spring days, a Friday afternoon. We were out getting ice cream and when we got back in the car, we both had missed calls. After listening to the voicemail, my stomach dropped, the mom said.

Their son received an abnormal newborn screening result for SMA, a rare genetic disorder caused by deficiency of the survival motor neuron protein (SMN1), resulting in progressive degeneration and irreversible loss of cells in the spinal cord and brainstem. Without treatment, the decreased level of the SMN protein leads to muscle weakness, and wasting atrophy of muscles used for movement. Most babies diagnosed with this disorder will have weak mobility, typically shown in the extremities, such as limp legs and arms, before six-months of life. This debilitating and often fatal muscle weakness can lead to an individual not being able to perform the basic functions of life, like breathing and swallowing, eventually leading to death by two or three-years-old. SMA is the leading cause of infant mortality from a single gene disorder, and its prevalence is one per 10,000 births globally.

This is a pretty devastating genetic disease, said Zheng (Jane) Fan, MD, pediatric neurologist, co-investigator for the Early Check pilot study. The severity of the disease depends on the genetic mutation subtype. For SMA babies, they have no copies of the SMN1 gene. Their disease severity depends on the number of copies of the SMN2 gene, which serves as a backup copy for the SMN1 gene, she said.

The Early Check results showed that the son had an absent SMN1 gene. A follow-up appointment was scheduled for the family to visit UNC School of Medicines Clinical & Translational Research Center (CTRC) the following Tuesday for confirmatory testing and to see how many copies of the SMN2 gene were present. For the parents, it was a long, grueling three days full of questions about whether or not their son was going to live.

We basically mourned the loss of our son that entire weekend before our visit to Chapel Hill, said the dad.

The confirmatory testing tells how many copies of the SMN2 gene are present. If there are three or more copies of the SMN2 gene, a baby could have a moderate form of SMA, whereas if there are two or less copies of SMN2, it could lead to a more severe form. Results showed that the son had three back-up copies of the SMN2 gene.

All the types of SMA are caused by the same gene variant, but are different in severity that will influence the age of onset and how quickly and severe it will manifest. Classification is based on the clinical age of onset and rate of regression, said Yael Shiloh-Malawsky, MD, pediatric neurologist and associate professor in the UNC Department of Neurology. With the more severe form, a child will never gain the milestone of sitting. This is Type I. Type II are kids who will be able to sit, but will never gain independent walking and later on can lose the ability to sit without help. Type III are children who gain walking, and later on will have decline in their strength.

Just looking at the child with the naked eye, no one could tell that he had a debilitating disorder forming on the inside. No symptoms were shown at all. For this particular case, the son fell within the Type II range.

For babies with Type I or II, the recommendation is to start treatment as soon as possible, said Dr. Fan.

We didnt even think treatment was an option, said the mom as her eyes begin to fill with tears.

During our first appointment with Dr. Fan, she showed us videos of children jumping rope and running. Children who had SMA, but received treatment. We never thought our son was going to be able to do any of those things, her voice trembled.

Life-Saving New Treatments for SMA

New medical advances are changing the course of SMA by helping thousands of children diagnosed with the disease experience better outcomes. For this family specifically, treatments were narrowed down to two choices; Spinraza, an FDA approved drug at $125,000 per one dose that is continued every four months for the duration of the individuals life, or they could choose the recent FDA approved gene therapy called Zolgensma, a $2-million dollar one-time treatment.

Time was of the essence. With SMA, once symptoms start to appear, its a red flag that motor neurons have already been lost. A decision needed to be made quickly.

After discussions with our pediatrician, Dr. Fan, Dr. Shiloh, and other medical professionals, we decided to choose Zolgensma, said the mom.

Zolgensma, the first gene therapy approved to treat children with SMA less than two-years-old, is a one-time intravenous infusion that takes about an hour. It involves a safe virus, AAV9, that delivers a fully functional human SMN1 gene to the targeted motor neurons, which in turn improves muscle movement and function, and also improves survival and quality of life.

Multiple testing went underway to see if the child was eligible for the Zolgensma treatment.

If the baby had antibodies against the AAV9 virus, then the gene therapy wouldnt have been effective, Dr. Fan said. This is because once the therapy penetrates the blood, the antibodies would kill the virus, even though the virus was harmless and carrying potentially life-saving cargo.

Luckily, test results showed that the baby did not have antibodies against the virus. It took two weeks for the treatment to be approved from insurance and to be delivered to UNC Childrens Hospital. Then on April 21st at eight-weeks-old, the baby became the first at UNC Medical Center to receive the life-saving gene therapy treatment.

I have a real appreciation for our doctors. They are so brilliant and they want to use that towards the good of our children. Theres hope, said the dad.

From checking in, receiving the treatment, to monitoring for side effects, the whole process took about seven hours. After staying in town for a couple days, the family headed back home. However, the son was monitored continuously to check for potential side effects the biggest being elevated liver enzymes, due to an inflammatory response.

This baby tolerated the gene therapy treatment well, with no apparent side effects and his liver enzymes remained in normal range throughout the monitoring period, Dr. Fan said.

For children diagnosed with SMA Type II, muscle weakness develops between ages 6 and 12 months. However, because the Early Check newborn screening was available for SMA and the child received the gene therapy early before the onset of symptoms, the outcome is in his favor.

If the child had been born in a different state that already started newborn screening on a population basis, he would have been screened, but because North Carolina hadnt started screening for SMA yet, he wouldve been missed if his family hadnt signed up for the study. Its pretty remarkable, said Dr. Powell.

As of May 1, 2021, SMA has been part of newborn screening statewide, and North Carolina is among the more than 30 states with this screening.

Our expectation is that this child will have normal development, normal strength like any other baby, said Dr. Shiloh-Malawsky.

For now, the parents continue to be observant of their son while being cautiously optimistic.

Its the nature of parenting that youre going to worry about your child, said the mom. I was thinking it was a death sentence when I heard about my sons diagnosis. Were only three months into it, but from what the doctors have said, it doesnt have to be a death sentence. My son can live a fulfilling life. Were grateful for that.

So far, hes right on track for his physical therapy evaluation, and recently, he rolled over for the very first time, she said, and she smiled.

Written by Brittany Phillips, UNC Health Communications Specialist

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Baby First at UNC to Receive Gene Therapy for SMA, Thanks to Early Check Newborn Screening | Newsroom - UNC Health and UNC School of Medicine

COLUMBUS, OHIO A novel method of gene therapy is helping children born with a rare genetic disorder called AADC deficiency that causes severe physical and developmental disabilities. The study, led by researchers at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine, offers new hope to those living with incurable genetic and neurodegenerative diseases.

Research findings are published online in the journal Nature Communications.

This study describes the findings from the targeted delivery of gene therapy to midbrain to treat a rare deadly neurodevelopmental disorder in children with a neurogenetic disease, aromatic L-amino acid decarboxylase (AADC) deficiency characterized by deficient synthesis of dopamine and serotonin.

Only about 135 children worldwide are known to be missing the enzyme that produces dopamine in the central nervous system, which fuels pathways in the brain responsible for motor function and emotions. Without this enzyme, children lack muscle control, and are usually unable to speak, feed themselves or even hold up their head. They also suffer from seizure-like episodes called oculogyric crises that can last for hours.

Remarkably, these episodes are the first symptom to disappear after gene therapy surgery, and they never return, said study co-author Dr. Krystof Bankiewicz, professor of neurological surgery at Ohio State College of Medicine who leads the Bankiewicz Lab. In the months that follow, many patients experience life-changing improvements. Not only do they begin laughing and have improved mood, but many are able to begin speaking and even walking. They are making up for the time they lost during their abnormal development.

The directed gene therapy in seven children ages 4 to 9 who were infused with the viral vector resulted in dramatic improvement of symptoms, motor function and quality of life. Six children were treated at UCSF Benioff Childrens Hospital in San Francisco and one at Ohio State Wexner Medical Center. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future, Bankiewicz said.

During the gene therapy surgery, physicians infuse a benign virus programmed with specific DNA into precisely targeted areas of the brain. The infusion is delivered extremely slowly as surgeons monitor exactly how it spreads within the brain using real-time MRI imaging.

Really, what we're doing is introducing a different code to the cell, said Dr. James Brad Elder, director of neurosurgical oncology at Ohio State Wexner Medical Centers Neurological Institute. And we're watching the whole thing happen live. So we continuously repeat the MRI and we can see the infusion blossom within the desired nucleus.

Researchers believe this same method of gene therapy can be used to treat other genetic disorders as well as common neurodegenerative diseases, such as Parkinsons and Alzheimers disease. Clinical trials are underway to test this procedure in others living with debilitating and incurable neurological conditions.

The directed gene therapy, in these patients, resulted in dramatic improvement of symptoms, motor function and quality of life. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future.

The findings described in this study are the culmination of decades of work by teams from multiple academic institutions, including University of California San Francisco, Washington University in St. Louis, Medical Neurogenetics Laboratory in Atlanta, St. Louis Childrens Hospital and Nationwide Childrens Hospital in Columbus, Ohio.

The research was supported by the National Institute of Neurological Disorders and Stroke and foundational grants, including the AADC Research Trust, the Pediatric Neurotransmitter Disease Association and funding from The Ohio State University.

This work provides a framework for the treatment of other human nervous system genetic diseases. Its our hope that this will be first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner, Bankiewicz said.

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Your Healthy Family: New gene therapy providing hope for those with rare genetic disorders - KOAA.com Colorado Springs and Pueblo News

When she isnt pursuing her favorite heart-pumping activities of running, swimming, or cycling, Sharlene M. Day, a presidential associate professor of cardiovascular medicine and director of Translational Research for the Penn Cardiovascular Institute, is focused on the heart in another way; trying to unlock and treat the mysteries of genetic heart disease.

As part of her research at the Day Lab, Day integrates translational and clinical science to understand the full spectrum of genetic heart disease evolution and progression, from gene mutations in heart muscle cells to ways of predicting negative outcomes in patients. Clinically, she sees patients with hypertrophic cardiomyopathy, a condition where the heart muscle becomes thick making it harder for blood to leave the heart, and other genetic heart conditions at the Penn Center for Inherited Cardiac Disease, such as inherited arrhythmias, high blood cholesterol, Marfan syndrome and familial amyloidosis. Her research program primarily focuses on these same conditions.

A physician scientist, Day completed her residency, followed by a cardiology fellowship, and a postdoctoral research fellowship at the University of Michigan before joining the faculty there, and spent 24 years there before coming to Penn. Day was recruited to Penn Medicine to lead initiatives in translational research within the Cardiovascular Institute and to grow the clinical and academic mission in the Penn Center for Inherited Cardiovascular Disease.

Very early on in my training, I became fascinated with the interplay between genetics and cardiac physiology that manifest in very unique observable cardiac traits and complicated disease trajectories including both heart failure and arrhythmias, also known as irregular heartbeats, says Day.

This story is by Sophie Kluthe. Read more at Penn Medicine News.

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Getting to the heart of genetic cardiovascular diseases | Penn Today - Penn Today