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Hot Topics of the Day are picked by experts to capture the latest information and publications on public health genomics and precision health for various diseases and health topics. Sources include published scientific literature, reviews, blogs and popular press articles.

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256 hot topic(s) found with the query "Gene therapy"

Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action.
Vaidehi Jobanputra et al. NPJ Genom Med 2024 3 (1) 23 (Posted: Apr 01, 2024 9AM)

From the article: "GS has ushered in a new era in the diagnosis of genetic diseases, offering the potential for improved patient care. Now is the time for collective action to overcome challenges, implement best practices, and ensure that the benefits of GS are realized for all individuals affected by genetic diseases. Indeed, widespread and appropriate utilization of GS is critical for directing the emerging gene editing, gene therapy, and cell-based therapies for rare genetic disorders. Concerted policy, education, guideline, and care pathway efforts will drive significant advancements in precision medicine and improve health outcomes for patients with genetic conditions. "

Building CRISPR Gene Therapies for the Central Nervous System: A Review.
Sally E Salomonsson et al. JAMA Neurol 2024 1 (Posted: Jan 30, 2024 8AM)

From the abstract: "Gene editing using clustered regularly interspaced short palindromic repeats (CRISPR) holds the promise to arrest or cure monogenic disease if it can be determined which genetic change to create without inducing unintended cellular dysfunction and how to deliver this technology to the target organ reliably and safely. Clinical trials for blood and liver disorders, for which delivery of CRISPR is not limiting, show promise, yet no trials have begun for central nervous system (CNS) indications. "

Deaf boy can now hear after breakthrough gene treatment
Medical XPress, January 23, 2024 (Posted: Jan 25, 2024 8AM)

From the article: " Gene therapy for hearing loss is something that we physicians and scientists in the world of hearing loss have been working toward for over 20 years, and it is finally here. While the gene therapy we performed in our patient was to correct an abnormality in one, very rare gene, these studies may open the door for future use for some of the over 150 other genes that cause childhood hearing loss."

Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders.
Marlen C Lauffer et al. Commun Med (Lond) 2024 1 (1) 6 (Posted: Jan 22, 2024 8AM)

From the abstract:" We discuss which genetic disorders have the potential to benefit from a specific type of ASO approach, based on the pathophysiology of the disease and pathogenic variant type, as well as those disorders that might not be suitable for ASO therapies. We further explore additional aspects, such as the target tissues, intervention time points, and potential clinical benefits, which need to be considered before developing a compound. Overall, we provide an overview of the current potentials and limitations of ASO-based therapeutics for the treatment of monogenic disorders. "

How CRISPR gene editing could help treat Alzheimer’s
T Thompson, Nature, December 11, 2023 (Posted: Dec 12, 2023 9AM)

From the article: "Last month saw the first-ever approval of a gene therapy that uses the CRISPR–Cas9 gene-editing tool, a treatment for the blood conditions sickle-cell disease and ß-thalassaemia that works by precisely cutting out a faulty gene in people’s stem cells. Now, researchers in search of new treatments for Alzheimer’s disease are hoping to deploy similar strategies against forms of the disease that are caused by genetic mutations."

A new age of precision gene therapy.
Axel Schambach et al. Lancet 2023 11 (Posted: Nov 29, 2023 9AM)

From the abstract: "Gene therapy has become a clinical reality as market-approved advanced therapy medicinal products for the treatment of distinct monogenetic diseases and B-cell malignancies. This Therapeutic Review aims to explain how progress in genome editing technologies offers the possibility to expand both therapeutic options and the types of diseases that will become treatable. "

Public Health Genetics, Gene Therapy, and Duchenne Muscular Dystrophy
CDC Webinar, December 18, 2023 Brand (Posted: Nov 27, 2023 10AM)

From the website: "This webinar will review the population health impact of rare diseases such as DMD. Presenters will cover the genetics and clinical impact of DMD, the evolution of gene therapy, the development of FDA-approved gene therapy to treat the underlying protein deficiency that causes DMD, and the health equity challenges. "

Gene therapies for rare diseases are under threat. Scientists hope to save them- As industry steps aside, scientists seek innovative ways to make sure expensive treatments can reach people who need them.
H Ledford, Nature, October 6, 2023 (Posted: Oct 06, 2023 7AM)

From the article: "In the past two years, two gene therapies have been withdrawn from the European market for business reasons after earning regulators’ approval. Concern is mounting that other gene therapies for rare diseases will meet a similar fate, as might upcoming treatments that rely on the related technique of genome editing, which makes targeted DNA changes. "

Hemostasis - A Balancing Act.
H Marijke van den Berg et al. N Engl J Med 2023 8 (9) 853-856 (Posted: Aug 31, 2023 7AM)

From the paper: "It is reassuring that this first-in-class drug is effective in treating hemophilia A or B with inhibitors. Given its reported efficacy in both types of hemophilia without inhibitors, concizumab is evolving as an attractive therapeutic for all patients with hemophilia. In the bigger picture, these new treatment options need to be weighed against the possibility of cure of hemophilia through gene therapy: two adeno-associated virus (AAV) vector–based products have been approved for clinical use, and more are in the pipeline."

Realising the potential of gene therapies for rare and ultra-rare inherited diseases.
Claire Booth et al. Hum Gene Ther 2023 8 (Posted: Aug 30, 2023 9AM)

From the abstract: "Rare and ultra-rare diseases have been central to the field of gene therapy since its earliest stage, and we are now witnessing more and more effective treatments entering the clinical realm for patients in need. However, despite promising results across a range of rare diseases, transformative gene therapies may not be available and accessible to patients for non-medical reasons. Traditional regulatory and commercialisation pathways to licensed products seem to be prohibitive for ultra-small patient populations. Here we highlight some of the challenges of delivering gene therapies in rare diseases and discuss innovative solutions being proposed by the gene therapy community."

Gene Therapy in Patients with the Crigler-Najjar Syndrome.
Lorenzo D'Antiga et al. N Engl J Med 2023 8 (7) 620-631 (Posted: Aug 21, 2023 8AM)

A framework for identifying targets for individualized therapy in genetic disease.
et al. Nature 2023 7 (Posted: Jul 17, 2023 8AM)

Researchers have developed a system to classify genetic mutations that could be addressed by therapeutic interventions that use ‘splice-switching antisense oligonucleotides’. This framework identified multiple eligible mutations among 235 people with the genetic disorder ataxia–telangiectasia. An oligonucleotide that was specific to one of these mutations was advanced to a proof-of-concept individualized trial.

The FDA just approved another gene therapy. Here’s what to know about them
SA Yonah, Washington Post, July 1, 2023 (Posted: Jul 01, 2023 3PM)

The Food and Drug Administration approved a treatment that uses gene therapy to treat severe hemophilia A, a rare and sometimes fatal blood disorder. The new drug, Roctavian, could save people with the severe form of the disease from a lifetime of frequent injections. The drug’s maker expects about 2,500 of the estimated 6,500 Americans with severe hemophilia A to be eligible to receive the drug with its initial approval.

Suddenly, It Looks Like We’re in a Golden Age for Medicine We may be on the cusp of an era of astonishing innovation — the limits of which aren’t even clear yet.
DW Wells, New York Times. June 23, 2023 (Posted: Jun 24, 2023 10AM)

And although the very first person to receive Crispr gene therapy in the United States received it just four years ago, for sickle-cell disease, it has since been rolled out for testing on congenital blindness, heart disease, diabetes, cancer and H.I.V. So far only two applications for such treatments have been submitted to the F.D.A., but all told, some 400 million people worldwide are afflicted by one or more diseases arising from single-gene mutations that would be theoretically simple for Crispr to fix.

CRISPR Therapy Exceeds Targets in Thalassemia, Sickle Cell Disease
M Basset, Medpage today, June 13, 2023 (Posted: Jun 16, 2023 8AM)

Data from two pivotal trials suggest that a single infusion of the CRISPR-based gene therapy exagamglogene autotemcel (exa-cel) can provide a "functional cure" for patients with transfusion-dependent beta-thalassemia or severe sickle cell disease.

Muscular dystrophy gene therapy nears approval, but safety concerns linger Use of viruses poses significant risks and, for now, prevents retreatment if benefits fade
J Kaiser, Science, May 23, 2023 (Posted: May 27, 2023 7AM)

Because of a mutation in the gene for dystrophin, DMD patients lack functioning copies of the huge protein that serves as a shock absorber inside muscle fiber cells. Without it, muscle cells become damaged and gradually die. Patients usually end up using a wheelchair by age 12 and succumb to heart or respiratory problems by age 30. (Most are boys; the dystrophin gene is on the X chromosome, so girls have two copies and rarely develop DMD.) Existing therapies are only modestly effective.

Emerging Trends in Gene Therapy: Thalassemia as a Case Study
CDC Seminar— June 22, 2023, 2:00–3:00 PM ET Brand (Posted: May 17, 2023 11AM)

Although relatively new in terms of clinical application, several gene therapy-based treatments have, in recent years, received approval from the Food and Drug Administration (FDA) and begun to be used in real world settings in the United States. In addition, clinical trials using either gene transfer or genome editing continue to show promise, with the potential to impact treatment for patients with a wide range of hereditary disorders in the future. This webinar will showcase thalassemia as a case example in emerging approaches in gene therapy.

The gene-therapy revolution risks stalling if we don't talk about drug pricing.
et al. Nature 2023 4 (7958) 629-630 (Posted: Apr 29, 2023 3PM)

Seventy years from now, the world might look back on 2023 as a landmark, as well. This year could see the first authorization of a therapy based on CRISPR–Cas9 gene editing, that involves tweaking the DNA in the body’s non-reproductive (somatic) cells. But gene therapies currently carry eye-watering price tags, putting them out of the reach of many who need them. High prices could diminish the willingness of government funders to pay for gene-therapy research. And that, in turn, would make it harder for research institutions to continue to attract top talent to the field.

Contributions from medical geneticists in clinical trials of genetic therapies: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
LDM Pena et al, Genetics in Medicine, April 9, 2023 (Posted: Apr 10, 2023 7AM)

As of December 2022, 5 gene therapy products have already been granted FDA marketing approval for rare Mendelian diseases in the United States, and several others have been approved outside of the United States. In the coming years, this list is expected to grow substantially given the number of products under development. Medical geneticists have expertise that supports unique roles in the development of new genetic therapies, before study initiation (Preclinical), during clinical development (Clinical Trial), and after marketing approval (LTFU). LTFU, long-term follow-up; SAE, serious adverse event.

Conquering Alzheimer's: a look at the therapies of the future Researchers are looking to drug combinations, vaccines and gene therapy as they forge the next generation of treatments for the condition.
A Abbot, Nature, April 4, 2023 (Posted: Apr 04, 2023 6AM)

Hemophilia A Gene Therapy - Some Answers, More Questions.
Lindsey A George et al. The New England journal of medicine 2023 2 (8) 761-763 (Posted: Feb 23, 2023 9AM)

Within a growing therapeutic armamentarium, adeno-associated virus (AAV)–mediated gene transfer of factors VIII and IX has been in clinical development for two decades. Thus far, the development of a gene therapy for hemophilia has been an iterative process, with future successes predicated on the investigation of unexpected observations from clinical trials to then improve the next generation of vectors.

Access to gene therapy for rare diseases when commercialization is not fit for purpose.
Thomas Fox et al. Nature medicine 2023 2 (Posted: Feb 15, 2023 7AM)

Despite promising preclinical and clinical efficacy data, hematopoietic stem-cell gene therapies for inherited diseases have not been widely adopted into clinical practice. Ultra-rare diseases such as inborn errors of metabolism and inborn errors of immunity are, as their names suggest, individually rare diseases, affecting <1 in 50,000 people. However, such diseases have a profound impact on the lives of many individuals because of reduced life expectancy or chronic progressive morbidity.

Perspectives on Evolving Gene Therapy for X-Linked Retinitis Pigmentosa.
Sabyasachi Sengupta et al. JAMA ophthalmology 2023 2 (Posted: Feb 11, 2023 8AM)

Management of retinitis pigmentosa and other inherited retinal dystrophies has progressively evolved toward gene therapy, especially after the first successful treatment using an adeno-associated viral vector (AAV8) with gene delivery into retinal photoreceptors. The recently completed phase 1 XIRIUS trial has expanded this gene delivery approach to a potential treatment of X-linked retinitis pigmentosa (XLRP), commonly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene.

What It’s Like to Learn You’re Going to Live Longer Than You Expected
DJ Lamas, NY Times, February 6, 2023 (Posted: Feb 07, 2023 6AM)

Molly was born in 1988 with cystic fibrosis, a genetic disease that leads to an early death from lung failure. But Ms. Pam is now 34. And thanks to a new drug that has revolutionized the treatment of this disease, she will likely live to celebrate her ??40th and even 50th birthdays. Her life expectancy has shifted drastically within her lifetime. It is a remarkable and complicated experience. And as science races forward with gene therapy and targeted cancer treatments that promise to turn terminal disease into chronic illness, it is also a lesson in what might be ahead.

How gene therapy is emerging from its 'dark age'.
Gemma Conroy et al. Nature 2022 12 (7940) S24-S26 (Posted: Jan 30, 2023 3PM)

With emerging treatments such as FLT180a in the pipeline, the future is beginning to look better for people with debilitating genetic diseases, from blood disorders to eye conditions. And although gene therapy still has a way to go before it becomes a routine treatment, the wave of approvals and clinical trials signal that the dark age of gene therapy could finally be over. “It’s here to stay.”

Sources of Innovation in Gene Therapies - Approaches to Achieving Affordable Prices.
Kerstin N Vokinger et al. The New England journal of medicine 2023 1 (Posted: Jan 26, 2023 7AM)

Gene therapies are a fast-growing area of innovation and potentially hold great promise for clinical care. Most recently, a new gene therapy, etranacogene dezaparvovec (Hemgenix), was approved by the Food and Drug Administration (FDA) for use in adults with hemophilia B (factor IX deficiency); the cost of this one-time treatment has been estimated at $3.5 million. Since 2017, a total of 11 such treatments have been approved by the FDA.

THE EVOLVING ROLE OF MEDICAL GENETICISTS IN THE ERA OF GENE THERAPY: AN URGENCY TO PREPARE.
Vockley Jerry et al. Genetics in medicine : official journal of the American College of Medical Genetics 2023 1 100022 (Posted: Jan 22, 2023 8AM)

Medical geneticists have well-established roles in the direct management of many rare genetic diseases and often provide support in the diagnosis and care of patients with such diseases. Because an increasing number of gene therapies are likely to become available over the next decade, there is a need to better define the role of medical geneticists within current and future gene therapy pathways and prepare for their expected role within the context of this new treatment paradigm.

Accounting for diversity in the design of CRISPR-based therapeutic genome editing
K Saha, Nature Genetics, January 2, 2023 (Posted: Jan 02, 2023 0PM)

CRISPR cell and gene therapy have been designed largely with respect to a single reference human genome. A new study reveals how human genetic diversity could lead to off-target effects and presents a new tool to identify these risks.

Gene Therapy for Artemis-Deficient SCID
SY Pai, NEJM, December 22, 2022 (Posted: Dec 22, 2022 8AM)

Infants with severe combined immunodeficiency (SCID), a disease characterized by a failure of T-cell development, die of opportunistic infection unless treated. Standard allogeneic hematopoietic-cell transplantation has limitations due to immunologic differences between the patient and the donor. A recent study used an integrating viral vector to bring about gene “addition”. Gene addition takes advantage of the natural properties of certain types of viruses, including the lentiviruses, to integrate into the patient’s genome in a semirandom fashion.

Rare disease therapeutics: The future of medical genetics in a changing landscape
CD Connolly et al, Genetics in Medicine, December 7, 2022 (Posted: Dec 07, 2022 9AM)

Many therapeutic modalities are currently being investigated as potential avenues to provide disease-modifying treatments for patients affected by genetic disorders. Some of these modalities include small molecule, enzyme replacement, gene, messenger RNA, and gene editing therapies. Although it is impossible to determine how many therapeutics will become available for patients affected by genetic disorders, historical data on the probability of orphan drug approval by the FDA and the current gene therapy trials noted above provide an estimate of the number of gene therapies that may become FDA-approved therapies.

A Promising Trial Targets a Genetic Risk for Alzheimer’s
G Kolata, NY Times, December 2, 2022 (Posted: Dec 04, 2022 4PM)

Preliminary results offer hope that gene therapy can protect people with a version of the brain disease driven by a particular gene variant. Participants in the study are among the approximately 2 percent of people who have inherited a pair of copies of a gene, APOE4, which markedly increases their risk of Alzheimer’s.

Africa must participate in finding a gene therapy cure for sickle-cell disease.
Moshi Grace et al. Nature medicine 2022 10 (Posted: Oct 08, 2022 7AM)

SCD is a disease of global public heath significance, has a dismal effect on the quality of life of many people, and it is a major drain on human and health resources. Scientific collaboration is needed to prioritize treatments that are cost-effective in Africa, where most cases exist. For these interventions to be implemented in Africa, several barriers must be overcome. Barriers include under-funded healthcare systems, lack of appropriate infrastructure, and lack of manufacturing practice facilities.

Sickle Cell Disease and Gene Therapy — Patient and Physician Perspectives
NEJM, Youtube video, Septenber 2022 (Posted: Oct 03, 2022 6AM)

In this short documentary video from the New England Journal of Medicine (NEJM), patients and physicians partner both to highlight the experience of living with sickle cell disease and to discuss the pathophysiology of the disease and new treatment strategies, including gene therapy.

Sickle Cell Disease and Gene Therapy - Patient and Physician Perspectives.
DeBaun Michael et al. The New England journal of medicine 2022 9 (13) e28 (Posted: Sep 29, 2022 8AM)

In this short documentary video, patients and physicians partner both to highlight the experience of living with sickle cell disease and to discuss the pathophysiology of the disease and new treatment strategies, including gene therapy. Patients share their own stories of interactions with the health care system and explore the challenging topics of racial disparity and health equity. Physicians express a cautious optimism as they review the risks and benefits of gene therapy.

Monoclonal antibodies for malaria prevention.
Aleshnick Maya et al. Molecular therapy : the journal of the American Society of Gene Therapy 2022 4 (5) 1810-1821 (Posted: Aug 04, 2022 8AM)

Despite several approaches to prevent established infection, no single approach offers complete protection, so a multilayered approach is needed. One potential layer, the monoclonal antibody. opens in new tab, is the focus of a new trial. The authors describe protection conferred by a long-acting, next-generation monoclonal antibody against controlled human malaria infection in healthy persons.

Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency
STF Shih et al, IJNS, July 20, 2022 (Posted: Jul 21, 2022 7AM)

Over a 60-year time horizon, screening every newborn in the population and treating diagnosed SCID by early hematopoietic stem cell transplantation and SMA by gene therapy, would result in 95 QALYs gained per 100,000 newborns, and result in cost savings of USD 8.6 million. Sensitivity analysis indicates 97% of simulated results are considered cost-effective against commonly used willingness-to-pay thresholds. The introduction of combined NBS for SCID and SMA is good value for money from the long-term clinical and economic perspectives, representing a cost saving to governments in the long-term, as well as improving and saving lives

Early treatment is a lifeline for infants with SMA.
Sumner Charlotte J et al. Nature medicine 2022 7 (Posted: Jul 18, 2022 1PM)

In the phase 3 SPR1NT trial, pre-symptomatic gene therapy demonstrated impressive clinical outcomes in infants with a genetic diagnosis of spinal muscular atrophy (SMA); long-term safety follow-up of these patients must now be a key priority.

Will gene therapy comeback last?
H Ledford, Nature, May 31, 2022 (Posted: Jun 01, 2022 7AM)

After years of disappointment, gene-therapy research has undergone a renaissance, with several high-profile drug approvals and a string of promising clinical-trial results against devastating genetic diseases, including sickle-cell disease and some blood cancers. But as researchers attempt to develop treatments for new conditions, they are also trying to work out how to cope with worrying signs that immune responses to the therapies could hinder their efforts — and generate dangerous side effects.

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A
S Fong et al, Nature Medicine, April 11, 2022 (Posted: Apr 11, 2022 2PM)

Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans.

Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A
MC Ozelo et al, NEJM, March 17, 2022 (Posted: Mar 17, 2022 9AM)

We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors. In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis.

Prepare the Way for Hemophilia A Gene Therapy
CD Thornburg, NEJM, March 17, 2022 (Posted: Mar 17, 2022 9AM)

Valoctocogene roxaparvovec has been granted Regenerative Medicine Advanced Therapy and Breakthrough Therapy designations from the Food and Drug Administration. If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia.

Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial
E Magrin et al, Nature Medicine, January 24, 2022 (Posted: Jan 24, 2022 2PM)

Gene therapy for hemophilia A
K O'Leary, Nature Medicine, November 30, 2021 (Posted: Nov 30, 2021 9AM)

Hemophilia A is caused by gene mutations that lead to absence or dysfunction of clotting factor VIII, which manifests as frequent, spontaneous hemorrhage. In a phase 1/2 trial, an investigational gene therapy brought about sustained expression of clotting factor VII and a dramatic reduction in the bleeding rate.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A
LA George et al, NEJM, November 18, 2021 (Posted: Nov 18, 2021 5AM)

The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. In this phase 1–2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled. Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported.

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome
B Gentner et al, NEJM, November 18, 2021 (Posted: Nov 18, 2021 5AM)

Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. We are conducting an ongoing study involving eight children with MPSIH. The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system

Bespoke Gene Therapy Consortium
NIH, October 2021 Brand (Posted: Oct 27, 2021 0PM)

The AMP Bespoke Gene Therapy Consortium (BGTC) aims to develop platforms and standards that will speed the development and delivery of customized or ‘bespoke’ gene therapies that could treat the millions of people affected by rare diseases.

NIH, FDA and 15 private organizations join forces to increase effective gene therapies for rare diseases
NIH press release, October 27, 2021 Brand (Posted: Oct 27, 2021 0PM)

The National Institutes of Health, U.S. Food and Drug Administration, 10 pharmaceutical companies and five non-profit organizations have partnered to accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease. While there are approximately 7,000 rare diseases, only two heritable diseases currently have FDA-approved gene therapies.

Record number of gene-therapy trials, despite setbacks
C Arnold, Nature Medicine, August 2021 (Posted: Aug 15, 2021 3PM)

This rollercoaster ride is emblematic of the gene-therapy field’s recent growing pains, although safety concerns and lack of efficacy have not stopped the explosive growth in trials. Clinicaltrials.gov lists nearly 5,000 gene-therapy trials, and more than 100 trials of ASOs from around the world, more than ever before. But the long-term safety of some of these therapies remains unclear.

Gene therapies should be for all
Nature Medicine editorial, August 12, 2021 (Posted: Aug 13, 2021 8AM)

More than 200 phase 2 and 3 gene therapy trials are currently underway, which could translate into up to 40 new products’ being approved for clinical use in the next decade, and the potential eligibility of 1.09 million patients in the next 15 years. The availability of more gene therapy products will bring profound changes to the treatment landscape of many rare genetic diseases, which will offer for the first time potentially curative options for patients. Healthcare systems worldwide have to start preparing now to cope with the challenge of ensuring that all patients, not just a select few with financial means and privileged access to technology, can benefit from these innovative therapies.

Sickle-cell anemia gene therapy
O Alam, Nature Genetics, August 6, 2021 (Posted: Aug 09, 2021 0PM)

A new study demonstrates durable editing of the sickle-cell disease allele in the ß-globin gene into a non-pathogenic variant in human-patient hematopoietic stem and progenitor cells that were transplanted into mice. Editing successfully mediated phenotypic rescue, thus suggesting a potential one-time ABE treatment for sickle-cell disease.

How Designer DNA Is Changing Medicine - A genomic revolution is poised to cure sickle cell and other genetic diseases
C Barber, Scientific American, July 17, 2021 (Posted: Jul 19, 2021 6AM)

The next-generation technology, gene editing, is another level altogether. Gene editing enables scientists to precisely target abnormal genes of many organisms (bacteria, plants, animals), snip the DNA, then remove, replace or add new DNA at the incision site. “Imagine you have a car with a flat tire. Gene therapy is taking a fifth wheel and putting it somewhere on the car and hoping it runs. Gene editing is repairing the flat.”

Extending the reach of gene therapies means hurdling not just scientific barriers but prices, too
M Molteni, Stat News, July 2021 (Posted: Jul 18, 2021 7AM)

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
TS Pearson et al, Nat Comms, July 12, 2021 (Posted: Jul 12, 2021 11AM)

Aromatic L-amino acid decarboxylase deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency.

Landmark gene therapy trial points to a wider window to alter course of rare disease
M Molteni, Stat News, July 12, 2021 (Posted: Jul 12, 2021 11AM)

It was a small Phase 1 study designed only to test safety. Yet the striking results suggest not only a viable strategy to treat a neglected and devastating disease, but a possible upheaval of what neuroscientists think they know about the brain’s ability to make new connections once freed from a genetic death sentence.

Ethical challenges for a new generation of early-phase pediatric gene therapy trials.
Iyer Alexander A et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 7 (Posted: Jul 09, 2021 7AM)

After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities.

Gene therapy helps children with immunodeficiency
O'Leary, Nature Medicine, June 10, 2021 (Posted: Jun 11, 2021 7AM)

Adenosine deaminase (ADA) deficiency is a rare, inherited disorder that leads to potentially life-threatening severe combined immunodeficiency (ADA-SCID). Enzyme-replacement therapy provides only limited benefit and patients ultimately require a stem-cell transplant. A lentivirus-based treatment restores immune function with minimal side effects in children with adenosine deaminase deficiency.

Partial recovery of visual function in a blind patient after optogenetic therapy
JA Sahel et al, Nature Medicine, May 24, 2021 (Posted: May 25, 2021 7AM)

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles

‘N of 1’ therapies need a better model
AA Rus, Nature Medicine, May 24, 2021 (Posted: May 25, 2021 7AM)

Oligonucleotides offer therapeutic potential for patients with genetic disorders carrying unique mutations, but developing individualized therapies is not supported by the current process for drug development.

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.
Kohn Donald B et al. The New England journal of medicine 2021 5 (Posted: May 13, 2021 7AM)

We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.

Gene therapy needs a long-term approach
Editorial, Nature Medicine, April 16, 2021 (Posted: Apr 17, 2021 0PM)

Gene-therapy trials are on the rise, but more needs to be done to understand the long-term risks associated with this type of treatment. Safety concerns associated with gene therapy are not new and have been highly publicized. Most gene therapies are designed to achieve permanent or long-lasting effects in the human body, and this inherently increases the risk of delayed adverse events.

Genetic therapies offer new hope against incurable brain diseases - A class of drugs that silence the effects of faulty genes could help tackle brain diseases — but a halted clinical trial has brought the field up short.
D Kwon, Nature, April 6, 2021 (Posted: Apr 06, 2021 8AM)

The success of the early Huntington’s trial caught the attention of neurodegeneration researchers, because tangles of protein are a key feature of many such disorders. There was a lot of excitement about this, because it really opened up the doors to be able to do antisense trials for other neurodegenerative diseases.

Treatment boost for spinal muscular atrophy- A small molecule that acts as a splicing modifier shows promise as a non-invasive therapy for type 1 spinal muscular atrophy.
J Staal, Nature Medicine, March 31, 2021 (Posted: Apr 01, 2021 1PM)

Gene Therapy for Sickle Cell Disease-A Debt to Be Paid.
Ozuah Philip O et al. JAMA pediatrics 2021 3 (Posted: Mar 23, 2021 8AM)

Sickle cell disease, caused by a point mutation in DNA, a single amino acid substitution in a single gene, has long been recognized as a good target for gene therapy. The irony here is inescapable—some of the most underserved patients in the world are ideal candidates for the most advanced medical treatment yet conceived.

A Budget Impact Analysis of Gene Therapy for Sickle Cell Disease: The Medicaid Perspective.
DeMartino Patrick et al. JAMA pediatrics 2021 3 (Posted: Mar 23, 2021 8AM)

An estimated 5464 Medicaid enrollees would be eligible for the gene therapy nationally, with 2315 individuals in the 10 Medicaid programs of interest (16 per 100 000 enrollees). The model projected a mean 1-year budget impact of $29.96 million per state Medicaid program in the sample ($1.91 per member per month). A 5-year annuity payment reduced the short-term budget impact.This study suggests that a gene therapy for severe sickle cell disease is likely to produce a considerable budget impact for many Medicaid plans while potentially offering substantial benefit to patients.

Sickle Cell Treatment Not Linked to Cancer, Researchers Say
G Kolata, NY Times, March 10, 2021 (Posted: Mar 12, 2021 7AM)

Just a few weeks after a promising gene therapy for sickle cell disease seemed to have hit a roadblock, prospects for the treatment now look better. Preliminary data suggesting that it might cause cancer have not held up.

Gene therapy trials for sickle cell disease halted after two patients develop cancer
J Kaiser, Science, February 16, 2021 (Posted: Feb 22, 2021 4PM)

A company has stopped its clinical studies of a promising gene therapy for the blood disorder sickle cell disease after two people who participated developed leukemia-like cancer. The company is now investigating whether a virus it uses to deliver a therapeutic gene caused the cancers, reviving old concerns about the risks of this approach.

Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy
V Himic et al, EJHG, February 9, 2021 (Posted: Feb 10, 2021 9AM)

As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment.

Strategies for Treating Inherited Retinal Degeneration With Large Genes That Are Not Amenable to Adeno-Associated Virus–Based Gene Replacement Therapy
P Yang et al, JAMA Ophthalmology, January 28, 2021 (Posted: Jan 30, 2021 7AM)

onogenic inherited retinal degeneration occurs from variations in genes associated with critical biochemical or physiological pathways necessary for normal function of outer retinal cells, which, when deficient, create disease with substantial visual loss in patients. Gene replacement (or augmentation) therapy involves transporting a good copy of the defective gene along with a promoter to the affected cells of the retina.

Induction of Fetal Hemoglobin by Gene Therapy
MC Walters, NEJM, January 21, 2021 (Posted: Jan 21, 2021 1PM)

The topic of equitable access to novel therapies with curative intent for sickle cell disease commingles clinical, translational, and implementation science. The development of disease-modifying therapies for sickle cell disease was stunted for many years.

Assessment of rAAVrh.74.MHCK7.micro-dystrophin Gene Therapy Using Magnetic Resonance Imaging in Children With Duchenne Muscular Dystrophy
RJ Wilcocks et al, JAMA Network Open, January 4, 2021 (Posted: Jan 06, 2021 8AM)

Gene therapy using haematopoietic stem and progenitor cells.
Ferrari Giuliana et al. Nature reviews. Genetics 2020 Dec (Posted: Dec 14, 2020 8AM)

Haematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and ß-thalassaemia.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy
P Yu et al, Sci Trans Med, December 9, 2020 (Posted: Dec 10, 2020 8AM)

37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject’s right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period.

CRISPR gene therapy shows promise against blood diseases
H Ledford, Nature News, December 10, 2020 (Posted: Dec 09, 2020 10AM)

Researchers report early successes using genetic approaches to treat sickle-cell anemia and ß-thalassemia. The CRIPSR and RNA approaches take a different tack. They seek to boost expression of a form of hemoglobin that is normally produced in the fetus and then switched off shortly after birth.

PaVe-GT: Collaborative NIH Effort Aimed at Creating a Gene Therapy Playbook, Making Rare Disease Treatments More Accessible
NIH NCATS, November 30, 2020 Brand (Posted: Dec 03, 2020 9AM)

Only about 5% of the approximately 7,000 rare diseases have a treatment approved by the FDA. A new NIH initiative aims to make gene therapy development and clinical testing more streamlined and less expensive — and potentially more accessible to millions of people with rare diseases.

Turning genes into medicines—what have we learned from gene therapy drug development in the past decade?
KA High, Nature Comms, November 16, 2020 (Posted: Nov 17, 2020 8AM)

Gene and cell therapy products approved over the past decade in Europe and North America have provided new therapeutic options for single gene disorders and for hematologic malignancies. Lessons learned, and limitations identified, are reviewed.

The once and future gene therapy
K Bulaklak e al, Nature Comms, November 16, 2020 (Posted: Nov 17, 2020 8AM)

Gene therapy is at an inflection point. Recent successes in genetic medicine have paved the path for a broader second wave of therapies and laid the foundation for next-generation technologies. This comment summarizes recent advances and expectations for the near future.

Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial
L Kuehlwein et al, JAMA Dermatology, October 15, 2020 (Posted: Oct 16, 2020 7AM)

IN this longitudinal cohort study of 57 adults, 17 of the PDE6A variants appeared to be novel. Disease was highly symmetrical between right and left eyes, and visual impairment was mild or moderate in 90% of patients. These data suggest that PDE6A–retinitis pigmentosa may be amenable to gene therapy.

Gene therapy and gene correction: targets, progress, and challenges for treating human diseases
MC Kring et al, Gene Therapy, October 2020 (Posted: Oct 14, 2020 7AM)

The field of gene therapy has made significant strides over the last several decades toward the treatment of previously untreatable genetic disease. Gene therapy techniques have been aimed at mitigating disease features of recessive and dominant disorders, as well as several cancers and other diseases.

Opening the door to gene therapy for ALS
H Stower, Nature Medicine, August 7, 2020 (Posted: Aug 10, 2020 8AM)

Two studies show the potential of RNA-based gene-therapy approaches in the treatment of amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease that in 10% of patients is caused by a mutation in the gene encoding superoxide dismutase 1 (SOD1), and targeting this gene is a therapeutic approach in development.

Overview of the current status of gene therapy for primary immune deficiencies
CY Ku, J Allergy Clin Immunol, August 2020 (Posted: Aug 06, 2020 7AM)

Although common platforms of cells, vectors, or editing reagents are used for these disorders, each individual genetic cause of an immune deficiency requires its own vector or editing tools and a package of preclinical data on efficacy and safety to initiate clinical trials.

A Boy With Muscular Dystrophy Was Headed For A Wheelchair. Then Gene Therapy Arrived
J Hamilton, NPR, July 27, 2020 (Posted: Jul 27, 2020 8AM)

Nine boys with Duchenne have received gene therapy. Preliminary results on six of them, tested a year after treatment, showed they had improved strength and endurance at an age when boys with Duchenne usually become weaker. The success suggests that gene therapy could be poised to change the lives of thousands of children — usually boys —who have Duchenne.

Clearing the path for gene therapy
B Gyorgy, Sci Trans Med, July 8, 2020 (Posted: Jul 09, 2020 9AM)

Gene therapy is a clinical reality, and product development is progressing at an astonishing speed. According to a Food and Drug Administration commissioner statement, with 10 to 20 new approved products per year, gene and cell therapies may potentially represent up to 40% of all new drug output by 2025.

Gene and Stem Cell Therapies for Fetal Care- A Review
AE O'Connell, JAMA Pediatrics, June 29, 2020 (Posted: Jun 30, 2020 8AM)

Fetal stem cell and gene therapy bring important therapeutic opportunities for select disorders that present in the fetal and neonatal periods. While this field is in its infancy, these therapies are starting to be available clinically, and clinicians should be aware of their benefits and challenges.

Here’s how genes from covid-19 survivors could help you- Gene therapy could put an end to future pandemics.
A Regalado, MIT Tech Review, June 18, 2020 (Posted: Jun 19, 2020 6AM)

The special considerations of gene therapy for mitochondrial diseases
J Slone et al, NPJ Genomic Medicine, March 2, 2020 (Posted: Mar 03, 2020 8AM)

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR
JC Kapetanovic et al. Nature Medicine, February 24, 2020 (Posted: Feb 25, 2020 9AM)

Retinal gene therapy has shown great promise in treating retinitis pigmentosa, a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial. There were no notable safety concerns after subretinal delivery of an adeno-associated viral vector.

Investigational Hemophilia A Gene Therapy Shows Sustained Benefit
J Abbasi, JAMA, February 11, 2020 (Posted: Feb 12, 2020 8AM)

An experimental gene therapy for hemophilia A remained effective up to 3 years after a single infusion, researchers recently reported in the New England Journal of Medicine. Valoctocogene roxaparvovec encodes factor VIII, the blood-clotting protein that’s missing or low in people with hemophilia A, the most common form of the disease.

Lentiviral gene therapy for X-linked chronic granulomatous disease
DB Kohn et al, Nature Medicine, January 27, 2020 (Posted: Jan 28, 2020 7AM)

At 16, She’s a Pioneer in the Fight to Cure Sickle Cell Disease
NY Times, January 11, 2020 (Posted: Jan 12, 2020 2PM)

For more than half a century, scientists have known the cause of sickle cell disease, a single mutation in a gene. Millions of people are affected globally, a vast majority of them Africans. Has gene therapy finally arrived? Helen Obando is the youngest person ever to get a gene therapy that scientists hope will cure the disease, which afflicts 100,000 Americans.

Manufacturing: the next breakthrough in gene therapy
D Blumenthal, Stat News, December 18, 2019 (Posted: Dec 22, 2019 6PM)

Gene therapy is facing its biggest challenge yet
Nature, December 2019 (Posted: Dec 07, 2019 7AM)

After finally gaining traction as a potential treatment for certain genetic disorders, gene therapy tackles the challenge of sickle-cell disease.

Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis.
Collins Francis S et al. The New England journal of medicine 2019 Oct (Posted: Nov 04, 2019 8AM)

The journey to gene-based therapies for cystic fibrosis began with enthusiasm over the prospect of gene therapy. But the challenges of using gene transfer to achieve long-lasting correction in the airway proved daunting.

Gene-Based Cures for SCD and HIV
NIH, October 23, 2019 Brand (Posted: Oct 24, 2019 9AM)

The collaboration aims to produce gene-based candidate treatments for SCD and HIV that can be administered at scale via low-cost delivery systems and advance them toward clinical trials in the United States and in Africa for safety and effectiveness within the next seven to 10 years.

Genetic therapies for hearing loss: Accomplishments and remaining challenges.
Taiber Shahar et al. Neuroscience letters 2019 Oct 134527 (Posted: Oct 07, 2019 11AM)

A promising approach for developing treatments for genetic hearing loss is the most simplistic one, that of gene therapy. Gene therapy would intuitively be ideal for these conditions since it is directed at the very source of the problem. Recent achievements in this field in laboratory models spike hope and optimism among scientists, patients, and industry.

Advancing Gene-Targeted Therapies for Central Nervous System Disorders: Proceedings of a Workshop
NASEM, Workshop Proceedings, September 20, 2019 (Posted: Sep 20, 2019 10AM)

The workshop explored approaches for developing gene-targeted therapies for CNS disorders, including approaches that target nucleic acids, such as adeno-associated viruses, antisense oligonucleotides, and RNA interference, as well as gene product-targeted therapies. Participants explored lessons learned from both successful and unsuccessful programs.

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective
RT Oliynyk, BioRXIV, September 18, 2019 (Posted: Sep 19, 2019 9AM)

Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia
P Rio et al, Nature Medicine, September 9, 2019 (Posted: Sep 10, 2019 9AM)

First gene therapy for β-thalassemia approved
C Harrison, Nature Biotechnology, September 9, 2019 (Posted: Sep 10, 2019 9AM)

Gene Therapy for Choroideremia-Progress and Remaining Questions.
Duncan Jacque L et al. JAMA ophthalmology 2019 Aug (Posted: Sep 01, 2019 7AM)

Choroideremia is a promising candidate for gene replacement because, although the gene affected in choroideremia, CHM, is expressed ubiquitously, pathologic changes are limited to the eye. In choroideremia, retinal degeneration spares the central photoreceptors until late stages of the disease, providing a long therapeutic window to preserve visual acuity.

Mom says she'll fight for world's most expensive drug for daughter, costs $2 million
AJC, August 22, 2019 (Posted: Aug 22, 2019 9AM)

Spinal Muscular Atrophy is a genetic condition. It causes muscle weakness and can lead to death. If not treated, the condition causes respiratory issues where kids are unable to breathe on their own. Gene therapy treatment must be administered by the time the child is 2 years old. It is considered the world's most expensive drug.

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Disclaimer: Articles listed in Hot Topics of the Day are selected by Public Health Genomics Branch to provide current awareness of the scientific literature and news. Inclusion in the update does not necessarily represent the views of the Centers for Disease Control and Prevention nor does it imply endorsement of the article's methods or findings. CDC and DHHS assume no responsibility for the factual accuracy of the items presented. The selection, omission, or content of items does not imply any endorsement or other position taken by CDC or DHHS. Opinion, findings and conclusions expressed by the original authors of items included in the Clips, or persons quoted therein, are strictly their own and are in no way meant to represent the opinion or views of CDC or DHHS. References to publications, news sources, and non-CDC Websites are provided solely for informational purposes and do not imply endorsement by CDC or DHHS.
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