Medical science is starting to license and use drugs and procedures that change the genetic code inside the bodys cells, and to correct the bad code that can give rise to conditions such as cancer and the auto-immune diseases. Since HIV is a disease that results from a virus inserting such a piece of bad code into our genes, such therapies could be used to snip out that code and effect a cure.
This was what attendees at last months International AIDS Society Conference on HIV Science (IAS 2021) heard at the workshop on curing HIV. The workshop opened with two introductory talks by Professor Hans-Peter Kiem, the chair of gene therapy at the Fred Hutchinson Cancer Research Center in Seattle in the US (the Fred Hutch) and, in a joint presentation, by the Fred Hutchs Dr Jennifer Adair and Dr Cissy Kityo of the Joint Clinical Research Centre (JCRC) in Kampala, Uganda.
The latter talk was a sign of acknowledgement that, while the prospects for genetic medicine are brighter than ever before, their expense and sophistication do not fit well with the global epidemiology of HIV, which mainly affects the worlds poorest and most disadvantaged communities. Despite this, Fred Hutch and JCRC have embarked upon a joint research programme to develop within the next few years a genetic therapy treatment for HIV that could be realistically scaled up for use in lower-income settings.
A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.
A type of experimental treatment in which foreign genetic material (DNA or RNA) is inserted into a person's cells to prevent or fight disease.
To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a persons body, or permanently control the virus and render it unable to cause disease. A sterilising cure would completely eliminate the virus. A functional cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness.
The body's mechanisms for fighting infections and eradicating dysfunctional cells.
In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a host cell), HIV binds to the CD4 receptor and its coreceptor.
HIV cure research pioneer Dr Paula Cannon of the University of Southern California, chairing the session, said: After several decades of effort and false starts, gene therapies now hold out promise for diseases that were previously untreatable.
Hans-Peter Kiem acknowledged the pivotal role of community advocacy in supporting cure research, noting that his project, defeatHIV, was one of the first beneficiaries of a grant from the Martin Delaney Collaboratories, named after the celebrated US treatment activist who died in 2009.
The other factor that gave impetus to HIV cure research was, of course, the announcement that someone had been cured: Timothy Ray Brown, whose HIV elimination was first announced in 2008 and who came forward publicly in 2010. He died in 2019 from the leukaemia whose treatment led to his HIV cure but by then had had 13 years of post-HIV life. He had survived long enough to talk with Adam Castillejo, the second person cured of HIV, and encourage him to come forward too.
Timothy and Adams stories showed that HIV could be cured, and with a crude form of gene therapy too: cancer patients, they were both given bone marrow transplants from donors whose T-cells lacked the gene for the CCR5 receptor, which is necessary for nearly all HIV infection.
But there have only been two cures for two reasons: firstly, bone marrow transplant is itself a very risky procedure involving deleting and replacing the entire immune system of already sick patients. In 2014 Browns doctor, Gero Hutter, reported that Timothy Ray Brown was only one of out of eight patients on whom the procedure had been tried, but that all the others had died.
Secondly, compatible bone marrow donors are hard to come by as it is, and restricting them to the 1% or so of people who lack the CCR5 receptor, all of them of northern European ancestry, means very few people could benefit from this approach. Attempting transplant with T-cells that do not lack CCR5, in the hope that replacing the immune system with cells from a person without cancer will also get rid of their HIV anyway, has produced temporary periods of undetectable HIV off therapy, but the virus has always come back.
(People like Brown and Castillejo, whose HIV infection was cured by medical intervention, need to be distinguished from people who seem to have spontaneously cured themselves, such as Loreen Willenberg: such people are of course of great interest to cure researchers, but the trick is to make it happen consistently in other people.)
Brown and Castillejos cures, as transplants, were so-called allogenic, meaning that the HIV-resistant cells came from another person. Better would be autogenic transplants, in which immune system cells are taken from a person with HIV, genetically altered in the lab dish to make them resistant to HIV, and then re-introduced. This type of procedure written about for aidsmap as long ago as 2011 by treatment advocate Matt Sharp, who underwent one.
The repertoire of gene therapies is not restricted to CCR5 deletion. Gene therapy is immensely versatile, and could be used in a number of ways.
Instead of using gene therapy to make cells resistant to HIV, it could directly repair defective genes in cells by means of cut-and-paste technology such as CRISPR/Cas9. This is already being used in trials for some genetic conditions such as cystic fibrosis and sickle-cell anaemia. Given that HIV-infected cells are also defective in the sense that they contain lengths of foreign DNA that shouldnt be there, they are amenable to the same molecular editing. Early trials have produced promising results but the challenge, as it has been in a lot of gene therapy, is to ensure that the cells containing DNA are almost entirely eliminated.
One way of doing this is not to delete the HIV DNA from infected cells but to preferentially kill off the cells themselves by creating so-called chimeric antigen receptor (CAR) T-cells. These are T-lymphocytes whose genes have been modified so that their usual receptors such as CD4 or CD8 have been replaced with receptors attuned very specifically to antigens (foreign or unusual proteins) displayed by infected cells and cancer cells. A couple of CAR cell therapies are already licensed for cancers; the problem with HIV is that the reservoir cells do not display immune-stimulating antigens on their surfaces. This means that CAR T-cells would have to be used alongside drugs such as PD-1 inhibitors that stop the cells retreating into their quiescent reservoir phase, an approach demonstrated at IAS 2021.
A couple of other approaches could be used to produce either vaccines or cures. One is to engineer B-cells so they produce broadly neutralising antibodies. A way of tweaking them to do this, called germline targeting, is covered was also discussed at IAS 2021, but if we manage to generate B-cells that can do this, we could then in theory directly edit their genes to make them do the same thing.
"Timothy Ray Brown and Adam Castillejo were both given bone marrow transplants from donors whose T-cells lacked the gene for the CCR5 receptor."
The other way is to induce cells to make viral antigens or virus-like particles that the immune system then reacts to. Scientists have been working on this technique for 20 years and it triumphed last year when the Pfizer and Moderna vaccines against the SARS-CoV-2 virus had over 90% success in suppressing symptomatic COVID-19. These vaccines are not genetic engineering in the sense of altering the genome of cells; rather, they introduce a product of the genetic activation in cells, the messenger RNA that is produced when genes are read and which is sent out into the rest of the cell to tell it to make proteins.
However because HIV is more variable and less immunogenic than SARS-CoV-2, the vaccine induced by the RNA would have to be something that looked much more like a whole virus than just the bare spike protein induced by the Pfizer and Moderna vaccines. If there was such a vaccine could be used both therapeutically as well as in prevention, by stimulating an immune reaction to activated HIV-infected cells. Moderna have announced they will now resume the HIV vaccine research they were working on when COVID-19 hit.
The problem with all these more gentle procedures is that it has proved difficult to replace all the HIV-susceptible cells with the HIV-resistant or HIV-sensitised ones: although engraftment takes place, meaning that the autologous cells are not rejected by the body and are able to establish a population for some time (in some animal experiments, replacing as much as 90% of the native immune cells), eventually the unaltered immune cells tend to win out because the introduced cells lack the deep reservoir of replenishing cells.
Kiem said that the way scientists have been trying to get round this is to only select and alter so-called haematopoeic stem cells (HSCs). These rare and long-lived cells, found in the bone marrow, are the replenishing reservoir of the immune system. They differentiate when they reproduce and give rise to all the immune cells that do different things: CD4 and CD8 T-lymphocytes, B-cells that make antibodies, macrophages that engulf pathogens, dendritic cells, monocytes, natural killer cells, and others.
Altering HSCs genetically so that they are able to fight HIV in one way or another could in theory give rise to a persistent, HIV-resistant immune system. They could in theory lie in wait and be ready to produce effector cells of various types. They would be ready when a new HIV infection comes along (if used as a vaccine) or when HIV viral rebound happens and there is detectable virus in the body (if used as part of a cure). If a person with CAR-engineered stem cells could have repeated cycles of treatment interruption, their HIV reservoir could in theory slowly be deleted.
"Gene therapies are astonishingly expensive."
As mentioned above, although genetic medicine shows enormous promise, the complexity and expense of its techniques means that at present it is unlikely to benefit most people who really need it.
Hans-Peter Kiem said that currently about 60 million people have conditions that could benefit from gene therapy. The vast majority of these either have HIV (37 million) or haemoglobinopathies blood-malformation diseases such as sickle-cell anaemia and thalassaemia that are also concentrated in the lower-income world (20 million).
Dr Jennifer Adair, one of the first researchers to have proposed collaboration on gene therapies for HIV with African institutes, said that gene therapies have already been licensed for conditions such as thalassaemia, spinal muscular atrophy, T-cell lymphoma and a form of early-onset blindness.
But they are astonishingly expensive. The worlds most expensive drug tag goes, depending on which source you read, either to Zynteglo, a genetic medicine correcting malformed beta-haemoglobin and licensed in the US for thalassaemia, or Zolgensma, a drug licensed in Europe and given to children to correct the defective gene that results in spinal muscular atrophy.
Both cost about 1.8 million for a single dose. The price is not just due to the cost of the complex engineering used to make them, but because they are used to treat rare diseases and so have a small market.
At present the technology need to engineer autogenic genetically engineered cells is, if anything, even more expensive and complex than that needed to introduce allogenic cells. It can involve in the region of ten staff and a workspace of 50 square metres per patient. Recently a so-called gene therapy in a box has been made available that can reduce the area needed to produce autogenic genetically-engineered cells from 50 to less than one square metre, and the staff need to one or two, But what is really needed is genetic engineering in a shot; a therapy similar to a vector or RNA vaccine that can be introduced as an injection and produces the genetic changes needed within the body.
Undaunted by the challenges, the US National Institutes of Health are collaborating with the Bill and Melinda Gates foundation to work on a combined programme of HIV and sickle-cell-anaemia genetic therapy (given that something that works for one could be adapted to work with the other).
And the Fred Hutchinson Center has teamed up with the Joint Clinical Research Centre in Uganda with the very ambitious goal of making a genetic therapy that would be at least ready for human testing within two years in an African setting, and that could be scaled up to be economical for Africa if successful.
Dr Cissy Kityo of JCRC in Uganda told the conference that as of 2020, there were 373 trials of gene therapy products registered, of which 35 were in phase III efficacy trials. The global budget for regenerative medicine, which includes genetic therapy and related techniques, was $19.9 billion, having jumped by 30% since the previous year. The US Food and Drug Administration projects that based on the current rate of progress and the development pipeline, they may be licensing around 100 gene-therapy products a year by 2025.
This branch of medicine is no longer exotic, she said. Now steps have to be taken to trial gene therapies in the people who needed them most, and to turn the exotic into the affordable, she added.
- UC Davis Health's partnership in telegenomics improves accessibility to genetic medicine with telemedicine robots - The Aggie - The Aggie - September 5th, 2021
- What to expect at the FDA's two-day meeting on gene therapy safety - BioPharma Dive - September 5th, 2021
- Global DNA Sequencing Report 2021: There is a Move Toward a More Consumer-Focused Model - Yahoo Finance - September 5th, 2021
- Agathos Biologics Receives $900,000 from the North Dakota Bioscience Innovation Grant Program - Yahoo Finance - September 5th, 2021
- New gene therapies may soon treat dozens of rare diseases, but million-dollar price tags will put them out of reach for many - The Conversation US - September 5th, 2021
- An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and s... - Physician's Weekly - September 5th, 2021
- Intense exercise could trigger ALS in those with genetic risk - Livescience.com - September 5th, 2021
- UT Southwestern selected top health care employer in Texas by Forbes - UT Southwestern - September 5th, 2021
- Opinion: Gene editing can be leveraged for the greater good with appropriate regulations - Varsity - September 5th, 2021
- Beefing up livestock disaster assistance | Farm & Ranch | willistonherald.com - Williston Daily Herald - September 5th, 2021
- Precision Medicine Platform Aims to Advance Cancer Gene Therapies - HealthITAnalytics.com - February 11th, 2021
- Celebrate the Third Annual Medical Genetics Awareness Week April 13-16, 2021 - PRNewswire - February 11th, 2021
- The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine - February 11th, 2021
- Myriad Genetics to Participate in Multiple Upcoming Health and Technology Conferences - GlobeNewswire - February 11th, 2021
- Neurons from patient blood cells enable researchers to test treatments for genetic brain disease - Brown University - February 11th, 2021
- The science behind those afternoon naps Harvard Gazette - Harvard Gazette - February 11th, 2021
- Ensoma Launches to Pioneer Next-Generation In Vivo Approach to Deliver First Off-the-shelf Genomic Medicines - Business Wire - February 11th, 2021
- Im 28 and I Dont Know My Family HistoryHeres How That Affects My Health - Well+Good - February 11th, 2021
- Ensoma Launches with $70 Million Series A and Takeda Licensing Deal - BioSpace - February 11th, 2021
- Response to Cancer Immunotherapy May Be Affected by Genes We Carry from Birth - UCSF News Services - February 11th, 2021
- NeuBase Therapeutics Reports Financial Results for the First Quarter of Fiscal Year 2021 - GlobeNewswire - February 11th, 2021
- PM Modi Waives off Rs 6 Crore Tax on Imported Medicine for 6-month-old Baby Girl from Mumbai - News18 - February 11th, 2021
- GeneSight Psychotropic Test's Combinatorial Approach Proves Better than Single-Gene Testing at Predicting Patient Outcomes and Medication Blood Levels... - February 11th, 2021
- Reflections on the 20th Anniversary of the First Publication of the Human Genome - Scientific American - February 11th, 2021
- Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise - February 1st, 2021
- Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them - CNN - February 1st, 2021
- Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program - BioSpace - February 1st, 2021
- CCMB team identifies variants of genes that metabolise drugs - BusinessLine - February 1st, 2021
- Digbi Health's gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California's... - February 1st, 2021
- Copy number variations linked to autism have diverse but overlapping effects - Spectrum - February 1st, 2021
- Are Gene Therapies the Medicine of the Future? - BioSpace - February 1st, 2021
- Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer - Technology Networks - February 1st, 2021
- Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting - A Virtual Experience - PRNewswire - February 1st, 2021
- 4 New Life Sciences Licensing Deals and Investments to Watch - BioSpace - February 1st, 2021
- CRISPR Mutants - The Dawn of CRISPR Mutants - SAPIENS - SAPIENS - February 1st, 2021
- SMART Study Finds 22q11.2 Microdeletion Prevalence Much Higher than Expected - PRNewswire - February 1st, 2021
- Genomes, Maps, And How They Affect You - IFLScience - February 1st, 2021
- Are Phages Overlooked Mediators of Health and Disease? - The Scientist - February 1st, 2021
- Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia - MD Magazine - February 1st, 2021
- The First Targeted Therapy For Lung Cancer Patients With The KRAS Gene MutationExtraordinary Results With Sotorasib - SurvivorNet - February 1st, 2021
- Atsena Therapeutics Raises $55 Million Series A Financing to Advance LCA1 Gene Therapy Clinical Program, Two Preclinical Assets, and Novel Capsid... - December 17th, 2020
- Locanabio Announces $100 Million Series B Financing to Advance Portfolio of Novel RNA-Targeted Gene Therapies for Neurodegenerative, Neuromuscular and... - December 17th, 2020
- NeuBase Therapeutics Announces Positive Preclinical In Vivo Data for PATrOL-enabled Anti-gene for the Treatment of Myotonic Dystrophy Type 1 -... - December 17th, 2020
- Genetic Analysis Services Market: Uptake of Next-generation Sequencing and Multi-gene Tests to Drive Market - BioSpace - December 17th, 2020
- FDA Clears Genetic Modification in Pigs for Biomedicine and Food - The Scientist - December 17th, 2020
- Key Genes Related to Severe COVID-19 Infection Identified - The Scientist - December 17th, 2020
- UNLV Researcher on the Curious Case of COVID-19 Reinfection - UNLV NewsCenter - December 17th, 2020
- Genomics and medicine it's complicated | Health | willistonherald.com - Williston Daily Herald - December 17th, 2020
- Emedgene collaborates with Illumina to scale the interpretation of genomic data for rare diseases - PRNewswire - December 17th, 2020
- Polymerase Chain Reaction Market | Increased Outbreak of Infectious Diseases to Accentuate Demand in the Market - BioSpace - December 17th, 2020
- LogicBio Therapeutics names Daphne Karydas and Jeff Goater to Board of Directors - BioSpace - December 17th, 2020
- rBIO Achieves Crucial Milestone on Mission to Lower the Cost of Insulin by 30% - BioSpace - December 17th, 2020
- Report: More than 1,300 Medicines and Vaccines in Development to Help Fight Cancer - PRNewswire - December 17th, 2020
- San Diego's Locanabio raises $100 million for treatments aimed at degenerative diseases - The San Diego Union-Tribune - December 17th, 2020
- Worldwide SNP Genotyping Industry to 2025 - Pharmacogenomics Led the End-user Segment of the SNP Genotyping Market - ResearchAndMarkets.com - Business... - December 17th, 2020
- Potential Weakness in SARS-CoV-2 Discovered Single Protein Needed for COVID-19 Virus to Reproduce and Spread - SciTechDaily - December 17th, 2020
- Landing of $75M expansion of Texas-based Taysha adds to Triangle's growing gene therapy hub - WRAL Tech Wire - December 17th, 2020
- Track the Vax: What Do We Need to Know About the New Vaccines? - Everyday Health - December 17th, 2020
- Medical history from the year you were born - Quad City Times - December 5th, 2020
- Sarepta Therapeutics to Share Clinical Update for SRP-5051, its Investigational PPMO for the Treatment of Duchenne Muscular Dystrophy - GlobeNewswire - December 5th, 2020
- Biochip Market | Increased Popularity of Personalized Medicine to Boost the Market Growth | Technavio - Business Wire - December 5th, 2020
- December: Baby birth weight research | News and features - University of Bristol - December 5th, 2020
- Global Next Generation Sequencing Market (2020 to 2026) - Growth, Trends, Competitive Landscape, and Forecasts - GlobeNewswire - December 5th, 2020
- NIH researchers link cases of ALS and FTD to a mutation associated with Huntington's disease - National Institute on Aging - December 5th, 2020
- Precision Medicine Market Poised to Grow at 11.5% By 20227 - GlobeNewswire - December 5th, 2020
- Fact check: mRNA vaccines kept at very cold temperatures so that they do not break apart; COVID-19 vaccines will not genetically modify humans -... - December 5th, 2020
- Stoke Therapeutics Announces Presentations Related to the Company's Work to Advance STK-001, the First Potential New Medicine to Target the Underlying... - December 5th, 2020
- King George III's illness debunked as symptom 'caused by medicine prescribed to him' - Express - December 5th, 2020
- Stoke Therapeutics to Present at the Needham Virtual Epilepsy & Pain Specialty CNS Therapeutics Conference - Business Wire - December 5th, 2020
- Following the science: the writers who have made sense of Covid - The Guardian - December 5th, 2020
- Gene experts claim they identified human genes that can protect against Covid-19 - CNBC - November 23rd, 2020
- Genome Medical Reaches 90 Million Covered Lives in US - PRNewswire - November 23rd, 2020
- Sarepta Therapeutics Named One of The Boston Globe's Top Places to Work 2020 - GlobeNewswire - November 23rd, 2020
- New Study Highlights the Importance of Genetic Testing for Pancreatic Cancer Patients - PRNewswire - November 23rd, 2020
- Baylor Genetics Launches Combination Test for COVID-19 and Influenza A and B; Multi-Panel Test Seeks to Address Dilemma of "Overlapping symptoms... - November 23rd, 2020
- CHOP Researchers Reverse Severe Lymphatic Disorder in Patient with Noonan Syndrome by Targeting Genetic Pathway - BioSpace - November 23rd, 2020
- Myriad Genetics Announces Global Expansion of Myriad myChoice Tumor Testing in Europe and China - GlobeNewswire - November 23rd, 2020
- Epigenetics and pulmonary diseases in the horizon of precision medicine: a review - DocWire News - November 23rd, 2020
- Four years after landing in US, graduating ISU senior is on his way to medical school - Iowa State University News Service - November 23rd, 2020
- Lethal brain infections in mice thwarted by decoy molecule - Washington University School of Medicine in St. Louis - November 23rd, 2020