Category Archives: Gene Medicine

In 2019, researchers announced the discovery of an unusually resilient person a Colombian woman who carried a ticking time bomb in her genes that should have triggered an aggressive, early form of Alzheimers disease, starting in her 40s. But for three decades, the bomb didnt explode.

Scientists studied her DNA and scanned her remarkable brain, ultimately tracing her protection to a rare version of the APOE gene, called the Christchurch variant. She had two copies. The extraordinary story of Aliria Rosa Piedrahita de Villegas, who did eventually develop dementia in her 70s and died of cancer at age 77, offered inspiration for a disease that afflicts millions of people, for whom hope is often in short supply.

But she was just one patient. That left a nagging doubt: Could this case hold the key to a new way to stave off Alzheimers? Or was she a one-off?

In a study published Wednesday in the New England Journal of Medicine, researchers reported 27 members of the same extended Colombian family carry the genetic risk for Alzheimers, along with a single copy of Christchurch. Cognitive decline in this singular group was delayed by about five years suggesting that a drug that emulates the gene could have similar effects.

We are taught in medicine to be wary of not drawing too many conclusions from a single patient, said Joseph F. Arboleda-Velasquez, an associate scientist at Mass Eye and Ear in Boston and a co-author of the study. Maybe it was related to something she ate or didnt eat. Maybe its something related to the water in the house. The idea of finding 27 people some lived in the city, some lived in rural areas increases our confidence in the discovery and shows the results are reproducible.

Francisco Lopera, a neurologist at the University of Antioquia in Medelln, Colombia, began caring for patients suffering from an aggressive, inherited form of Alzheimers four decades ago.

Cognitive impairment began when people were in their mid-40s. Full-blown dementia developed before the age of 50. Patients died in their 60s. Researchers traced the disease to a mutation in the gene Presenilin 1, now known to be carried by about 1,200 people within an extended family.

Piedrahita de Villegas showed scientists that it was possible to defy this grim genetic destiny. But for an exceptional patient to turn into broader medical insight, scientists need confirmation that the gene is producing the beneficial effect and can do the same in other people.

People carry two copies of the APOE gene, one inherited from each parent. Having two copies of the Christchurch version, as Piedrahita de Villegas did, is rare, extremely rare, said Yakeel T. Quiroz, a clinical neuropsychologist at Massachusetts General Hospital. So they started to look for people with just one.

A man who carried the Alzheimers risk mutation and a copy of Christchurch provided an initial clue. Brain imaging at age 51, when he was diagnosed with mild cognitive impairment, revealed that his brain had elevated levels of plaques of the beta-amyloid protein, a telltale sign of Alzheimers. But intriguingly, he had limited tangles of a different Alzheimers related protein, called tau, and he developed mild dementia at age 54, years later than expected.

That was a signal that having one copy could have been protective, Quiroz said. The team found 26 other people with this genetic makeup. Not all the patients have developed cognitive impairment, but among those who have, symptoms were delayed, beginning five years later than those without Christchurch. Dementia was also delayed, by four years.

The discovery that a single copy of Christchurch provides a degree of protection is a hopeful clue for scientists trying to develop therapies. If two copies were necessary, the bar for a new drug might be impossibly high it would have to be extremely effective to have any benefit. But seeing a lower dose of the gene protect against the onset of disease is a good sign. It suggests even partly mimicking the Christchurch genes action could work.

I think this is a really important study, and the outcome is very meaningful, said Yadong Huang, director of the Center for Translational Advancement at Gladstone Institutes, an independent biomedical research organization based in San Francisco. Huang was not involved in the study, but his lab showed last year that the Christchurch mutation has benefits in mice prone to develop Alzheimers disease and in human brain cells in a dish. Still, he noted that until now there has been a critical gap in knowledge how it affects humans in the real world.

For years, Alzheimers research has tended to focus on clearing the sticky amyloid plaques that build up in the brain. A few therapies have shown success, but they are far from a cure. The new study shows the promise of a different biological target: drugs that imitate the rare Christchurch variant of the APOE gene.

John Hardy, a neurogeneticist at the U.K. Dementia Research Institute at the University College London said pharmaceutical companies have traditionally been less enthusiastic about APOE because it is a difficult target, but that is changing.

Interest has been growing, and this finding is part of the reason, Hardy wrote in an email.

As a next step, researchers have developed an experimental antibody drug that imitates Christchurch. When it was given to mice that were genetically tweaked to develop features of Alzheimers, they found the drug reduced buildup of tau tangles a sign that they are on the right path.

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Rare gene mutation helps people resist Alzheimer's disease - The Washington Post

BENITEC BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q)  Marketscreener.com

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BENITEC BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) - Marketscreener.com

CENTOGENE to Participate in Upcoming Conferences in February in the Lead Up to Rare Disease Day  Marketscreener.com

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CENTOGENE to Participate in Upcoming Conferences in February in the Lead Up to Rare Disease Day - Marketscreener.com

Summary

gene, unit of hereditary information that occupies a fixed position (locus) on a chromosome. Genes achieve their effects by directing the synthesis of proteins.

In eukaryotes (such as animals, plants, and fungi), genes are contained within the cell nucleus. The mitochondria (in animals) and the chloroplasts (in plants) also contain small subsets of genes distinct from the genes found in the nucleus. In prokaryotes (organisms lacking a distinct nucleus, such as bacteria), genes are contained in a single chromosome that is free-floating in the cell cytoplasm. Many bacteria also contain plasmidsextrachromosomal genetic elements with a small number of genes.

The number of genes in an organisms genome (the entire set of chromosomes) varies significantly between species. For example, whereas the human genome contains an estimated 20,000 to 25,000 genes, the genome of the bacterium Escherichia coli O157:H7 houses precisely 5,416 genes. Arabidopsis thalianathe first plant for which a complete genomic sequence was recoveredhas roughly 25,500 genes; its genome is one of the smallest known to plants. Among extant independently replicating organisms, the bacterium Mycoplasma genitalium has the fewest number of genes, just 517.

A brief treatment of genes follows. For full treatment, see heredity.

Genes are composed of deoxyribonucleic acid (DNA), except in some viruses, which have genes consisting of a closely related compound called ribonucleic acid (RNA). A DNA molecule is composed of two chains of nucleotides that wind about each other to resemble a twisted ladder. The sides of the ladder are made up of sugars and phosphates, and the rungs are formed by bonded pairs of nitrogenous bases. These bases are adenine (A), guanine (G), cytosine (C), and thymine (T). An A on one chain bonds to a T on the other (thus forming an AT ladder rung); similarly, a C on one chain bonds to a G on the other. If the bonds between the bases are broken, the two chains unwind, and free nucleotides within the cell attach themselves to the exposed bases of the now-separated chains. The free nucleotides line up along each chain according to the base-pairing ruleA bonds to T, C bonds to G. This process results in the creation of two identical DNA molecules from one original and is the method by which hereditary information is passed from one generation of cells to the next.

The sequence of bases along a strand of DNA determines the genetic code. When the product of a particular gene is needed, the portion of the DNA molecule that contains that gene will split. Through the process of transcription, a strand of RNA with bases complementary to those of the gene is created from the free nucleotides in the cell. (RNA has the base uracil [U] instead of thymine, so A and U form base pairs during RNA synthesis.) This single chain of RNA, called messenger RNA (mRNA), then passes to the organelles called ribosomes, where the process of translation, or protein synthesis, takes place. During translation, a second type of RNA, transfer RNA (tRNA), matches up the nucleotides on mRNA with specific amino acids. Each set of three nucleotides codes for one amino acid. The series of amino acids built according to the sequence of nucleotides forms a polypeptide chain; all proteins are made from one or more linked polypeptide chains.

Experiments conducted in the 1940s indicated one gene being responsible for the assembly of one enzyme, or one polypeptide chain. This is known as the one geneone enzyme hypothesis. However, since this discovery, it has been realized that not all genes encode an enzyme and that some enzymes are made up of several short polypeptides encoded by two or more genes.

Experiments have shown that many of the genes within the cells of organisms are inactive much or even all of the time. Thus, at any time, in both eukaryotes and prokaryotes, it seems that a gene can be switched on or off. The regulation of genes between eukaryotes and prokaryotes differs in important ways.

The process by which genes are activated and deactivated in bacteria is well characterized. Bacteria have three types of genes: structural, operator, and regulator. Structural genes code for the synthesis of specific polypeptides. Operator genes contain the code necessary to begin the process of transcribing the DNA message of one or more structural genes into mRNA. Thus, structural genes are linked to an operator gene in a functional unit called an operon. Ultimately, the activity of the operon is controlled by a regulator gene, which produces a small protein molecule called a repressor. The repressor binds to the operator gene and prevents it from initiating the synthesis of the protein called for by the operon. The presence or absence of certain repressor molecules determines whether the operon is off or on. As mentioned, this model applies to bacteria.

The genes of eukaryotes, which do not have operons, are regulated independently. The series of events associated with gene expression in higher organisms involves multiple levels of regulation and is often influenced by the presence or absence of molecules called transcription factors. These factors influence the fundamental level of gene control, which is the rate of transcription, and may function as activators or enhancers. Specific transcription factors regulate the production of RNA from genes at certain times and in certain types of cells. Transcription factors often bind to the promoter, or regulatory region, found in the genes of higher organisms. Following transcription, introns (noncoding nucleotide sequences) are excised from the primary transcript through processes known as editing and splicing. The result of these processes is a functional strand of mRNA. For most genes this is a routine step in the production of mRNA, but in some genes there are multiple ways to splice the primary transcript, resulting in different mRNAs, which in turn result in different proteins. Some genes also are controlled at the translational and posttranslational levels.

Mutations occur when the number or order of bases in a gene is disrupted. Nucleotides can be deleted, doubled, rearranged, or replaced, each alteration having a particular effect. Mutation generally has little or no effect, but, when it does alter an organism, the change may be lethal or cause disease. A beneficial mutation will rise in frequency within a population until it becomes the norm.

For more information on the influence of genetic mutations in humans and other organisms, see human genetic disease and evolution.

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Gene | Definition, Structure, Expression, & Facts | Britannica

When Rylae-Ann Poulin was a year old, she didnt crawl or babble like other kids her age. A rare genetic disorder kept her from even lifting her head. Her parents took turns holding her upright at night just so she could breathe comfortably and sleep.

Then, months later. doctors delivered gene therapy directly to her brain.

Now the 4-year-old is walking, running, swimming, reading and riding horses just doing so many amazing things that doctors once said were impossible, said her mother, Judy Wei.

READ MORE: Gene therapy was a boys last chance to stop leukemia. And it worked.

Rylae-Ann, who lives with her family in Bangkok, was among the first to benefit from a new way of delivering gene therapy attacking diseases inside the brain that experts believe holds great promise for treating a host of brain disorders.

Her treatment recently became the first brain-delivered gene therapy after its approval in Europe and the United Kingdom for AADC deficiency, a disorder that interferes with the way cells in the nervous system communicate. New Jersey drugmaker PTC Therapeutics plans to seek U.S. approval this year.

Meanwhile, about 30 U.S. studies testing gene therapy to the brain for various disorders are ongoing, according to the National Institutes of Health. One, led by Dr. Krystof Bankiewicz at Ohio State University, also targets AADC deficiency. Others test treatments for disorders such as Alzheimers, Parkinsons and Huntingtons.

Challenges remain, especially with diseases caused by more than a single gene. But scientists say the evidence supporting this approach is mounting opening a new frontier in the fight against disorders afflicting our most complex and mysterious organ.

Theres a lot of exciting times ahead of us, said Bankiewicz, a neurosurgeon. Were seeing some breakthroughs.

The most dramatic of those breakthroughs involve Rylae-Anns disease, which is caused by mutations in a gene needed for an enzyme that helps make neurotransmitters like dopamine and serotonin, the bodys chemical messengers. The one-time treatment delivers a working version of the gene.

At around 3 months old, Rylae-Ann began having spells her parents thought were seizures her eyes would roll back and her muscles would tense. Fluid sometimes got into her lungs after feedings, sending her to the emergency room. Doctors thought she might have epilepsy or cerebral palsy.

Around that time, Weis brother sent her a Facebook post about a child in Taiwan with AADC deficiency. The extremely rare disorder afflicts about 135 children worldwide, many in that country. Wei, who was born in Taiwan, and her husband, Richard Poulin III, sought out a doctor there who correctly diagnosed Rylae-Ann. They learned she could qualify for a gene therapy clinical trial in Taiwan.

Though they were nervous about the prospect of brain surgery, they realized she likely wouldnt live past 4 years old without it.

WATCH: Researchers look for link between air pollution and brain disease

Rylae-Ann had the treatment at 18 months old on November 13, 2019 which her parents have dubbed her reborn day. Doctors delivered it during minimally invasive surgery, with a thin tube through a hole in the skull. A harmless virus carried in a functioning version of the gene.

It gets put into the brain cells and then the brain cells make the (neurotransmitter) dopamine, said Stuart Peltz, CEO of PTC Therapeutics.

Company officials said all patients in their clinical trials showed motor and cognitive improvements. Some of them, Peltz said, could eventually stand and walk, and continue getting better over time.

Bankiewicz said all 40 or so patients in his teams NIH-funded study also saw significant improvements. His surgical approach is more involved and delivers the treatment to a different part of the brain. It targets relevant circuits in the brain, Bankiewicz said, like planting seeds that cause ivy to sprout and spread.

Its really amazing work, said Jill Morris, a program director with the National Institute of Neurological Disorders and Stroke, which helped pay for the research. And he has seen a lot of consistency between patients.

One is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian got gene therapy in 2019, shortly before her 5th birthday. Two months later, she held her head up for the first time. She soon started using her hands and reaching for hugs. Seven months after surgery, she sat up on her own.

When the world was crumbling around us with COVID, we were at our house celebrating like it was the biggest party of our lives because Rian was just crushing so many milestones that were impossible for so long, said her mom, Shillann Rodriguez-Pena. Its a completely different life now.

Scientists say there are challenges to overcome before this approach becomes widespread for more common brain diseases.

For example, the timing of treatment is an issue. Generally, earlier in life is better because diseases can cause a cascade of problems over the years. Also, disorders with more complex causes like Alzheimers are tougher to treat with gene therapy.

When youre correcting one gene, you know exactly where the target is, said Morris.

Ryan Gilbert, a biomedical engineer at New Yorks Rensselaer Polytechnic Institute, said there can also be issues with the gene-carrying virus, which can potentially insert genetic information in an indiscriminate way. Gilbert and other researchers are working on other delivery methods, such as messenger RNA the technology used in many COVID-19 vaccines to deliver a genetic payload to the nucleus of cells.

Scientists are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But that requires getting around the blood-brain barrier, an inherent roadblock designed to keep viruses and other germs that may be circulating in the bloodstream out of the brain.

A more practical hurdle is cost. The price of gene therapies, borne mostly by insurers and governments, can run into the millions. The one-time PTC therapy, called Upstaza, costs more than $3 million in Europe, for example.

But drugmakers say they are committed to ensuring people get the treatments they need. And researchers are confident they can overcome the remaining scientific obstacles to this approach.

So I would say gene therapy can be leveraged for many sorts of brain diseases and disorders, Gilbert said. In the future, youre going to see more technology doing these kinds of things.

The families of Rylae-Ann and Rian said they hope other families dealing with devastating genetic diseases will someday get to see the transformations theyve seen. Both girls are continuing to improve. Rian is playing, eating all sorts of foods, learning to walk and working on language. Rylae-Ann is in preschool, has started a ballet class, and is reading at a kindergarten level.

When her dad picks her up, she runs to me just gives me a hug and says, I love you, Daddy. he said. Its like its a normal day, and thats all we ever wanted as parents.

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New gene therapy delivers treatment directly to brain

Indian Pharma Congress: Gene-cell therapy, preventive medicine future of health care, says expert  Economic Times

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Indian Pharma Congress: Gene-cell therapy, preventive medicine future of health care, says expert - Economic Times

A blood test that identifies people at higher risk of miscarriage? Thats the goal of this award-winning Rutgers med student.  The Philadelphia Inquirer

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A blood test that identifies people at higher risk of miscarriage? Thats the goal of this award-winning Rutgers med student. - The Philadelphia...

References:

1. NIH Genetics Home Reference. What is a Gene? https://ghr.nlm.nih.gov/primer/basics/gene. Accessed February 10, 2020.

2. Forbes. How Many Possible Combinations of DNA Are There? https://www.forbes.com/sites/quora/2017/01/20/how-many-possible-combinations-of-dna-are-there/. Accessed February 10, 2020.

3. NIH National Human Genome Research Institute. Genetic Disorders. https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders. Accessed February 10, 2020.

4. NIH Genetics Home Reference. How Can Gene Mutations Affect Health and Development? https://ghr.nlm.nih.gov/primer/mutationsanddisorders/mutationscausedisease. Accessed February 10, 2020.

5. NIH Genetics Home Reference. How does Gene Therapy Work? https://ghr.nlm.nih.gov/primer/therapy/procedures. Accessed February 10, 2020.

6. NIH Genetics Home Reference. What is Gene Therapy? https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed February 10, 2020.

7. Data on file. Pfizer Inc, New York, NY.

8. Haasteren J, Hyde S, Gill D. Lessons Learned From Lung and Liver In-Vivo Gene Therapy: Implications for the Future. Expert Opin Biol Ther. 2018;18(9):959-972.

9. Gowing G, Svendsen S, Svendsen CS. Ex Vivo Gene Therapy for the Treatment of Neurological Disorders. Prog Brain Res. 2017;230:99-132.

10. NIH National Human Genome Research Institute. What is Genome Editing? https://www.genome.gov/about-genomics/policy-issues/what-is-Genome-Editing. Accessed February 10, 2020.

11. Carroll D. Genome Engineering with Zinc-Finger Nucleases. Genetics. 2011;188(4):773-782.

12. Unniyampurath U, Krishnan M, et al. RNA Interference in the Age of CRISPR: Will CRISPR Interfere with RNAi? Int J Mol Sci. 2016;17(3):291.

13. Your Genome. Facts: What is Gene Therapy? http://www.yourgenome.org/facts/what-isgene-therapy. Accessed February 10, 2020.

14. Arruda VR, Favaro P, Finn JD. Strategies to Modulate Immune Responses: A New Frontier for Gene Therapy. Mol Ther. 2009;17(9):14921503.

15. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122(1):23-36.

16. Payne J. Antibody and antigen tests. Patient Platform Limited Web site. https://patient.info/health/antibody-and-antigen-tests. Accessed February 10, 2020.

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Gene Therapy: Genes As Medicine | Pfizer

How Genomics will ensure a risk-free and beneficial treatment for good health and well-being  The Financial Express

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How Genomics will ensure a risk-free and beneficial treatment for good health and well-being - The Financial Express

As described in Section 3033 of the 21st Century Cures Act, a drug is eligible for regenerative medicine advanced therapy (RMAT) designation if:

Based on FDAs interpretation of Section 506(g) of the Federal Food, Drug, and Cosmetic Act (as added by Section 3033 of the 21st Century Cures Act), certain human gene therapies and xenogeneic cell products may also meet the definition of a regenerative medicine therapy. For more information on FDAs definition of regenerative medicine therapies, refer to the Guidance for Industry, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions.

The request for RMAT designation must be made either concurrently with submission of an Investigational New Drug application (IND) or as an amendment to an existing IND. We will not grant a RMAT designation if an IND is on hold or is placed on hold during the designation review.

You may submit a request for RMAT designation to:

Food and Drug AdministrationCenter for Biologics Evaluation and ResearchOffice of Tissues and Advanced TherapiesDocument Control Center10903 New Hampshire AvenueWO71, G112Silver Spring, MD 20993-0002

If the RMAT designation request is submitted to your IND as an amendment, the cover letter should specify that the submission contains a REQUEST FOR REGENERATIVE MEDICINE ADVANCED THERAPY DESIGNATION in bold, uppercase letters. If the request is submitted with an initial IND, the cover letter should specify that the submission contains both an INITIAL INVESTIGATIONAL NEW DRUG SUBMISSION and REQUEST FOR REGENERATIVE MEDICINE ADVANCED THERAPY DESIGNATION in bold, upper case letters.

No later than 60 calendar days after receipt of the designation request, the Office of Tissues and Advanced Therapies (OTAT) will notify the sponsor as to whether RMAT designation has been granted. If OTAT determines that the RMAT designation request was incomplete or that the drug development program does not meet the criteria for RMAT designation, OTAT will include a written description of the rationale for such determination.

10/06/2021

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Regenerative Medicine Advanced Therapy Designation | FDA