Of the 7,000 known rare diseases affecting 350 to 400 million people worldwide, most have a genetic basis and it often comes down to a single gene that is wreaking havoc and harming the person’s health. Until recently, it was impossible to replace that one gene and save the patient. Much work has been done to map the human genome and develop techniques and tools necessary for gene therapy to realize the promise of treatment for these rare diseases. Here are nine reasons that the treatment of rare diseases will be big in 2025:

1. Remote participation will eliminate the need for travel for treatment

Rare diseases impact more people than cancer and AIDS combined. While we can say that about 1% of a nation’s population has a rare disease, altogether this is an immense number. Moreover, the American Journal of Managed Care (AJMC) reported that a 2019 study published in the European Journal of Human Genetics found that “approximately 4% of the total world population is affected by a rare disease at any given time, according to new research on 3,585 rare diseases.” The number of individuals with rare diseases can be quite large in many nations, with the emotional toll and cost of care reaching beyond the patient. New technologies in development will make it possible to reach rare disease patients remotely, without the need to physically travel to a different country for a trial. Harsha Rajasimha, Ph.D., founder and CEO of Jeeva Informatics Solutions Inc. described this in a previous article, Treatment of Rare Diseases: What You Need to Know. Rajasimha stressed the importance of remote participation since, without remote access, a participation depends on “the patient’s ability to travel and their zip code.”

2. It is now possible to determine the precise gene responsible for a monogenic disease.

One of the enduring benefits of the global effort to map the human genome is the ability to use the knowledge attained for a variety of purposes. Another important factor related to rare disease treatment is that there is a genetic basis for most rare diseases. Most are monogenic – diseases caused by an error in a single gene occurring in all cells of the body. Once identified, this error can potentially be cured with gene therapy. With the necessary information from gene sequencing in hand, the next step in creating a cure is to find a doctor or researcher with a thorough understanding of that specific genetic defect. Once that is accomplished, as was the case for Amber Freed, as we discussed in a previous article, the researcher will not only be familiar with the genetic condition but possibly have recommendations on how to treat it.

3. Orphan Drug Status provides many benefits

The Orphan Drug Act of 1983 made it possible for those with Orphan Drug Status to benefit from a range of incentives for those developing treatments for populations that meet the criteria. Irene Tennant, AGT’s VP of Clinical Product Development and Regulatory Affairs, discusses the tax credits, market exclusivity, and waiver of significant fees in-depth in Benefits of FDA Orphan Drug Designation: What You Need to Know.

4. Base editors can fix the point mutation

Researchers often know precisely what they must do to fix the error; they must replace the error with a working gene. “But for most point mutations that cause genetic diseases, simply cutting the already-mutated gene won’t benefit patients because the function of the mutated gene needs to be restored, not further disrupted,” said chemical biologist David Liu in his recent TED Talk. To solve this problem, Liu’s team developed molecular machines known as base editors. This new genome editing approach uses components from CRISPR systems to “directly convert one base to another without disrupting the rest of the gene.”.

5. 80% there on day one

The use of existing viral vector platforms and other technologies can speed the process of developing a treatment because researchers don’t have to start from scratch. It also reduces the costs associated with finding a treatment by using existing methods. AGT CEO Jeff Galvin says, “What we’ve done is create a platform of combinable components that can be mixed and matched to cure a myriad of diseases. It’s very much like maintaining a library of software subroutines. Such a collection of components makes it easy for you to create a solution on the existing foundation that already has the common elements of gene and cell therapy that span broad areas of disease control, starting the drug developer up to 80% of the way done on day one, and leaving them only the details that are particular to their target disease. It is sort of like an ‘iPhone for disease cures’ where curing a disease is like writing an app”.

3. “One-and-done” treatments make it possible to cure a patient.

One-and-done treatments are those treatments that take a single application to bring about a lasting effect or cure. By using viruses that carry DNA, gene therapy allows us, says Galvin, “to crack open these viruses, scoop out that viral DNA, and then replace it with other DNA that actually improves your health, improves the operation of the cell. We’re essentially converting viruses into updates for the operating system of your “self.” The result is a one-time treatment that replaces the incorrect gene forever.” The potential for such a cure will continue to put the focus on rare disease treatment.

7. Elimination of a potential impediment

One of the biggest problems with curing monogenic diseases is the immune response mounted by the patient’s own body. Known as graft vs. host disease, it can result in the death of the patient. This can occur when “you put a missing protein back in the body,” says Galvin, “because you’ve grown up all your life without that protein, your immune system will recognize that as an invader and try to attack it.” That is holding up a lot of work right now. Galvin says that researchers are “going to find a way to fix that, and that’s going to open the door to many different diseases.”

8. The other 20%

The good news is that gene therapy holds promise for other rare diseases. In Gene Therapy: More than Monogenic Disease, contributing author and Senior Biotechnology Analyst John Vandermosten provides a brief review of three programs using gene therapy for diseases that are not among the 80% that are monogenic. Vandermosten writes, “Gene therapy is a natural fit for addressing monogenic diseases; however, its application is much broader, and there are numerous programs underway that address other classes of disease in innovative ways.”

9. Gene therapy is no longer the stuff of science fiction or wishful thinking.

Treatment of rare diseases is within our grasp. As more work is done and more tools are created, the cost for each treatment will fall in the same way that the cost of desktop computers fell with ongoing innovation. For instance, Galvin recounts in his webinar, Cell and Gene Therapy: Discovering the Clinical & Commercial Potential, that in the same way smartphones have become available the world over as prices decline, gene therapy will become as ubiquitously available as the technology matures and moves down the cost curve.

Why 2025?

There are many factors in play that will make 2025 a big year for the treatment of rare diseases. Access to trials will become available to more patients through remote participation. Identification of the precise gene responsible for monogenic diseases will make it possible to explore life-saving treatments. The benefits obtained through the Orphan Drug Designation for pharmaceutical companies developing treatments will continue to be a positive factor. The combined use of base editors that can correct a point mutation, along with platforms and tools that are readily available can bring companies almost all of the way towards a successful treatment on day one. Combine this with one-and-done treatments that can be lifesaving, and in a few years it will be feasible to tackle these rare diseases in an efficient, cost-effective, and productive way. All told, today’s science and technology achievements hold great promise for the treatment of rare diseases in 2025.

Published on AGT

Factors to consider when launching your long-distance project

As the global economy has grown and become ever-more interconnected, the need for collaboration across time zones and borders has become increasingly important. People need real-time access to information during working hours that may occur at any point in a 24-hour period. Information captured around the globe needs to be stored in a mutually accessible form and location.

The GenomeTrakr is an international network of labs that began with an FDA pilot program in 2012. By 2018, the program had attained its stated milestones. The GenomeTrakr utilizes whole genome sequencing (WGS) to produce detailed genetic information from foods and foodborne pathogens to support outbreak investigations. An international network is essential because the food we eat comes from a number of different countries. Until the GenomeTrakr, tracing a foodborne illness back through the steps it took to reach a consumer’s plate had been time consuming, if not impossible. Today, the ability to enter information for the pathogen and “make a match” with the information entered for a food tested in the field results in identification of the source of the pathogen in a matter of days or less.

What it takes to make a virtual collaboration work

Any form of collaboration requires a willingness to work together toward a common goal. At first glance, that seems obvious and uncomplicated. Pick a goal. Get to work. Celebrate success along the way. We all know, however, that it’s often the case that a collaboration doesn’t work as planned. Somewhere along the line, trust is lost, misunderstandings occur, communication breaks down. The result is a missed opportunity that costs everyone involved time and money.

Related Webinar: Leading Teams Remotely

The data and analysis are maintained by the stakeholder with the necessary resources and charter. The purpose of the US National Center for Biotechnology Information (NCBI) is to advance science and health by providing access to biomedical and genomic information. Having the NCBI serve as the host while making the database available to anyone in the world at no charge and publishing daily reports that make it possible for contributors to see how new pathogens relate to existing data is a logical fit. Also, the NCBI is in the position to standardize the fields and the structure of the data input so that it is directly comparable across all users.

Especially when a collaboration involves the use of a new technology, as was the case with the GenomeTrakr, stakeholders in key roles must have the requisite knowledge, ability, and infrastructure to carry out their part. It may mean reaching out to organizations or people with the unique skills required, even if you don’t have an established relationship with them, if the result will be a stronger team.

Participating labs are vetted to ensure quality before becoming part of the network. The labs preparing the WGS and entering the information into the GenomeTrakr need to be vetted and approved by a preset process to ensure that all of the labs meet the same requirements and standards. This is necessary because, as is the case with any collaboration, the team will only be as strong as its weakest link. Also, those collaborating need to be able to trust the information coming from others on the project. When stakeholders are not local, the need to ensure consistent quality of the sites and at the sites is essential.

The technology is clear and well-defined. The GenomeTrakr cannot function without the detailed genetic information obtained through the use of WGS. This information essentially creates a fingerprint for a pathogen. Any one of them may one day be identified as the source of an outbreak. There are a number of acceptable ways to collect samples from individual foods and the WGS process is inherently uniform. As a result, there is a significant level of confidence in the accuracy of the WGS information obtained.

A personal connection is still essential. Virtual collaborations serve a useful function. Virtual meetings with far-flung collaborators have replaced most in-person meetings. Email and texts have taken the place of many phone conversations. All of this is well and good, as long as team members and stakeholders are able to forge the working relationships that are the keystone of an effective collaboration. It’s not enough to have formal, timed video calls where the discussion is focused on the project and only the project. Some interactions must be a bit more freeform so that those collaborating have a sense of one another. This doesn’t need to be a formal affair; in fact, many people find that they get to “know” one another through simple email exchanges that largely focus on the task at hand. The end result will be a virtual collaboration that thrives.

Published on Lab Manager

Thinking creatively can bring new purpose to everyday items.

Lab equipment is expensive. Often, it’s designed for a specific purpose. When that purpose is met by other equipment or a newer product with slightly different specs that is brought into the lab, material and equipment that is still “good” becomes redundant or useless before its time. Lab managers can rid the lab of these items by selling them to another lab, bringing cash into the lab for future purchases in the process. They can also recycle the equipment at no or minimal cost to the lab, but with a negative impact on the environment. Repurposing—the use of a piece of equipment for a different purpose—is a third option. It does not bring cash in from a sale, but it can keep cash from flowing out for a purchase. It also obviates the need for the expenditure of energy required to recycle the item in question.

Why repurpose?

As companies and nations work to reduce their environmental footprint, repurposing is on the rise. Unlike disposal or recycling, repurposing neither adds to the amount of material headed for a landfill nor uses new resources in the form of energy, transportation, and labor in the creation of a recycled product. Repurposing extends the life of a product by adding a period of use to the production, use, and disposal cycle of that product. Sometimes, equipment can be repurposed for a use that is similar to the original purpose. These instances are generally obvious. At other times, a bit of creativity is required.

Ten opportunities to repurpose

As long as the equipment or material in your lab that you are looking to repurpose is not adding to your environmental footprint or taking away from your bottom line, there are many ways to repurpose it with a new function. Here are 10 to get you started:

1. Carts and carriers: It’s often the case that the equipment that sat on the cart or was transported in the carrier was sold or recycled, leaving the transport portion behind and available for further use. Among other things, a cart or carrier can be used for files, books, or specimens that must be moved from one location to another—once clearly marked for that purpose—during their processing.

2. Shelving and storage units: Stationary shelving can limit the possibilities, yet it can still be repurposed. Rather than holding the equipment needed for the original use, assign those shelves the purpose of holding clean lab equipment, mitts, and eyewear. A storage unit, especially one that rolls, can house the materials required for routine day-to-day operations at different locations within the lab. When not in use, the unit can be tucked out of the way. When in use, it can be right where it is needed.

3. Paper goods: When equipment leaves the lab or takes on a new purpose, logbooks are left behind. Yet, a system for tracking performance or data can easily be modified to a different use. Change the column headings. Break the data on the page into units or groupings that are meaningful to the new process. The logs can be used to capture data before it is entered into a computer, or they can be used for meeting notes and annotations of journal articles or research studies that are of interest to those in the lab.

4. Filter paper and filters: Using filter papers to filter tea may be taking the notion of repurposing a few steps beyond what your lab is willing to do. Then again, everything you can put to a new use before it leaves the lab on its way to be recycled or dumped is a plus for the planet, and it’s already sitting there in the lab. Can the filter papers be used as coasters or for cleanups in the sink area of the coffee room? Is it possible to trim a filter in a frame while maintaining its integrity and use it in a new process?

5. Glassware: Once you get past glassware’s obvious suitability as a vessel for liquids ranging from water for plants to sun-brewed iced tea, a number of other possibilities come to mind. Having the glassware cut to heights that meet specific uses as a way to achieve this makes a lot of sense. Glassware with a height of a few inches makes a perfect container for paperclips, push pins, and binder clips, to name a few. Glassware cut to a height a bit shorter than pens or pencils provides a perfect pencil holder. Turning the glassware on its side and gluing it along the length will give you cubbyholes that stand up to use.

6. Protective gear: Mitts and aprons—these things are designed to protect people during their work. They can also be used to protect surfaces in day-to-day use. Mitts cut to a circle can be used under hot coffee pots. Mitts can also be cut to size and pulled up around the sides of a coffee pot to insulate the pot. Aprons make good chair covers in the kitchen area or the company commons.

7. Cleaning solutions and tools: A cleanser meant for one piece of equipment may be just as effective when used for another piece of equipment. It may even be suitable for general cleaning tasks around the lab. Be sure to check it out and see before trashing it, or using it. The same goes for tools that were a perfect fit for the nooks and crannies of one piece of equipment. Look around the lab to see if the tools work as well with something else.

8. Washing centers: Washing centers, cleaning stations—whatever you call the designated sink area for cleaning equipment in your lab—it’s likely that everything you need to clean equipment, draw filtered water, and get a supply of ice is within inches of each other. Efficiency like that should be maintained. Do the drying racks work with your new equipment? Is the current sink deep enough? Is it time to upgrade to a system that fills vessels by voice command? This is your chance to work with what you have to give it a try.

9. Sterilizing equipment and special-purpose machines: This equipment is generally expensive and manufactured to spec. However, if you have equipment for sterilizing or spinning samples, check to see if these capabilities are on the wish list of someone in your lab. If it’s practical to do so, one person’s old piece of equipment could just be someone else’s new and prized piece of equipment.

10. Workbenches: Chances are, you’ll always need spaces for lab personnel to work. When one set of workbenches is about to be replaced with the next new thing, stop for a moment. Is there a way to use these old benches? Often the benches are fixed in place. What other function could take place in that area? Could they be used as desks? Would their use in this way free up space in another part of the lab, making it possible for you to make a change you’ve wanted to make for quite some time? Could some communal activities take place in that space, freeing up room in the common area for something else—like a foosball table? While you’re at it, could you trick a workbench out as a ping pong table?

Repurposing your equipment and materials in the lab is well worth the time in both financial and environmental terms. As a result, your lab makes fewer purchases, and the space, energy, and labor required for recycling your equipment can be put to more productive use. That’s definitely a win-win.

Published on Lab Manager

More than 32 million people have died from AIDS-related illnesses since the start of the epidemic in 1981, making HIV/AIDS one of the greatest public health threats the world has known. Since it was first identified nearly 40 years ago, trillions of dollars have been spent by governments and private individuals on efforts to find effective treatments, vaccines, and a cure. The virus itself is surprisingly small and simple, and researchers know a great deal about the way HIV is contracted and makes its way through the body. However, to date, the only effective treatment is antiretroviral therapy (ART), which halts the progress of the virus.

It’s true that the use of ART has slowed the spread of HIV infection and reduced the number of deaths since the peak in 2004, there are still 38 million people living with HIV in the world today.  While ART prevents AIDS and prolongs life in those infected with HIV, it does so at a significant cost in quality-of-life. In short, they are not a cure. With so great an effort on a global scale, why has it been so difficult to find an HIV cure?

Here are five reasons an HIV cure remains elusive:

Retrovirus & Mutation

HIV is a retrovirus, carrying its genetic material in a single strand of RNA. Normal viruses carry genetic material, yet are unable to reproduce on their own. The genetic material in HIV’s RNA is introduced into a living cell where it is transcribed using the enzyme reverse transcriptase into DNA, which then integrates into the host’s DNA inside the nucleus. Once this takes place, the new sequence of viral DNA can be transcribed into viral RNA, allowing the virus to spread throughout the body. Reverse transcription, recombination, and short generation times for certain viruses, particularly HIV, are error prone and lead to frequent mutations.

In a 2017 paper, Recent advances in understanding evolution, for the F1000Research open access publishing platform, authors Andrews and Rowland-Jones of the University of Oxford identify these frequent mutations as “a major contributing factor in the failure of the immune system to eradicate the virus.” In addition, since each mutation makes it more difficult for treatments to recognize the virus, the virus evolves at what the authors describe as the highest recorded biological mutation rate currently known to science. The combination of the process and the mutations due to errors in the process results is one reason that HIV is exceedingly difficult to treat, let alone cure, with a single drug.

T Cells

Another major impediment in the search for an HIV Cure is the fact that HIV attacks CD4+ cells, more commonly referred to as Helper T cells. These T cells play a vital role in the functioning of a healthy immune system. By first invading and then commandeering the cell for its own viral purposes, HIV impedes the immune system in two ways: it reduces the number of functional T cells (because HIV infects them) and it ruptures the cellular membrane which kills the cell.

T cells can also die due to pyroptosis, apoptosis and attack by CD8+ T cells that recognize the infection.  HIV makes use of the prevalence of T cells to gain a hold in the individual’s body. Without the protection of the CD4+ T cells, the infected person will likely contract an opportunistic infection or unchecked form of cancer that results in death.

Latent Reservoirs

Not all HIV- infected cells are active simultaneously. During the very early stages of the HIV infection, some of the infected cells do not produce new copies of the virus. As a result,  latent, resting HIV virus cells can remain in “reservoirs” in the lymphoid tissues and other locations in the immune system for months, or even years. Current antiretroviral treatments (ARTs) are unable to eliminate these HIV infected cells because they are not circulating in the blood. This is a problem for the person infected with HIV because these cells can become active at any time.

In a recent ScienceDaily article, Scientists identify a new potential reservoir of latent HIV, the latent reservoirs were deemed “the main obstacle to curing HIV/AIDS.” A Gladstone visiting scientist, Nadia Roan, and her team, identified cells that “preferentially support latent infection by HIV.” The cells have a surface protein, CD127, and are “found in tissues such as lymph nodes…” Roan concluded, “our findings suggest that CD127 cells from tissues may be an important population to target for an HIV cure.” This is the case because the ability to “inactivate” infected cells that are not circulating is essential to a full, functional cure.

Cure vs Eradication

While ARTs are not a cure, this cocktail of drugs halts the progress of HIV to AIDS by targeting HIV at a different stage in its replication cycle. As a result, existing ARTs make it possible for those with HIV to live a nearly normal lifespan with the caveat that they must take medication on a regular basis while living with uncertainty over HIV’s reemergence. Essentially, antiretrovirals have changed what was formerly a death sentence to a life sentence. For many, the continued use of ARTs, in lieu of the search for a cure, forms the basis of their approach. UNAIDS is one such organization that is working toward the eradication of the disease by 2030 rather than a cure.

UNAIDS’ 90-90-90 target for the “post 2015 era” does not require a call. A disease can be eradicated – no longer actively infecting people – without the existence of a cure. This is the intention of UNAIDS, to prevent new HIV infections by meeting a series of targets. The targets call for people to first gain awareness of their HIV status, then to begin treatment, and then to suppress the virus through the use of ARTs and behaviors informed by their HIV status. As a result of this approach the number of new infections is expected to drop dramatically, making it less and less likely that new infections will occur.

However, a shortcoming of the move to eradicate rather than cure is that in times of upheaval, such as that caused by COVID-19, efforts to work toward eradication are in danger of being sidelined. In May, the UN issued a “wake-up call” to remind global leaders of the ongoing need for treatment in the areas of the world where the largest loss of life is most likely to occur if the spread of the disease is not prevented. Eradication is a positive goal for preserving life for future generations, but again, it is not a cure for the 38 million of people currently living with HIV.

Differing Definitions of HIV Cure

It seems simple enough to agree on what it means to bring about an HIV cure, yet there are two different types of cure envisioned. One is the sterilized cure, in which there is no trace of HIV in the body. The other is a functional cure, in which the HIV viral load will be kept below the level of detection without the use of antiretroviral therapy (ART). In the case of a functional cure, the infected person would not need to be on antiretroviral medication, would not experience the effects of HIV, and would not transmit the virus to anyone else. This is a cure because there would be no need for ART – ever – as opposed to a remission, in which there might be a recurrence of the disease. American Gene Technologies’ (AGT’s) upcoming Phase 1 Clinical Trial of their HIV Cure Program is for a functional cure.

Conclusion

The discovery of a cure for HIV/AIDS is notoriously difficult for reasons related to both science and approach. The mechanism of the virus in the body makes it difficult to cure because HIV invades and then commandeers the T cells responsible for defeating it. This reduces the number of functional T cells and ruptures their cellular membrane in the process. HIV also mutates at one of the fastest rates known to science, so far making it impossible to treat with a single drug. The virus can also hide, latent, in lymphoid tissues and other locations where it escapes detection.

The lack of agreement on the approach to take also impedes the discovery of an HIV cure because it results in the lack of a global effort focused on a single goal. Whether eradication is enough or a cure is necessary impacts where funds and efforts are spent. For those living with HIV/AIDS, or those who become infected during eradication efforts, the potential diversion of funds to eradicate over a cure is likely to leave the use of ARTs – for the rest of their lives – their only recourse.

Another impediment to progress toward an HIV cure that is related to a disagreement in approach is the question of what constitutes a cure. Is it a sterilized cure in which no trace of the disease remains? Is it a functional cure in which the disease is present but not capable of progressing to AIDS, or being transmitted? Is remission through the use of ARTs a cure if it calls for the daily medication with a cocktail of toxic drugs? Because each of these options will require funding and talent, the pursuit of several will diminish the resources for each.

For AGT, the goal is clear. Researchers have devoted decades to creating a functional cure for HIV/AIDS. For them, the bottom line is that neither ARTs nor the push for eradication will make it possible for the 38 million people currently living with HIV/AIDS to lead a healthy life without the need for ongoing medication. Their Phase I study at clinical sites in Baltimore and Washington D.C., beginning in the Fall of 2020 with their AGT103-T, shows promise for a single-dose cure for this lethal disease.

AGT sponsored this article to highlight the importance of continuing HIV cure research until a cure is found. AGT’s HIV Cure Program lead candidate for a functional cure is moving into clinical trials in 2020-2021.

Status of the Clinical Trial

On August 11, 2020, AGT announced approval by the FDA to begin Phase 1, the first human clinical trial for AGT’s lead HIV program. AGT will conduct its Phase 1 study at clinical sites in the Baltimore/D.C. area. AGT expects that these sites will begin enrollment in the Fall of 2020.

AGT’s Phase 1 study clinicaltrials.gov identifier number is NCT04561258 and the study ID is AGT-HC168. For information about AGT103-T Phase 1 study, its status, and the clinical site information, view it on clinicaltrials.gov by clicking the button below. https://clinicaltrials.gov/ct2/show/NCT04561258

Additional Resources:

https://www.unaids.org/sites/default/files/media_asset/UNAIDS_with-your-help_en.pdf

https://www.pedaids.org/2015/02/18/hiv-101-the-difference-between-control-elimination-and-eradication/

Published on AGT

Researchers have been working on an HIV Cure since the first reports of the illness appeared in 1981. We now have effective treatment in the form of a cocktail of antiretroviral drugs that stop the HIV virus’s progression to full-blown AIDS, but It is not a cure. Despite their benefits, antiretrovirals bring a shortened lifespan and impaired quality of life due to side effects from these toxic drugs ranging from bone loss and heart disease to diabetes and kidney damage.

As researchers around the world focus on finding treatments or vaccines for COVID-19, clinical trials and research pursuing a wide range of other conditions have been suspended or delayed. While the challenge of working remotely and within the constraints imposed by the pandemic is a factor affecting HIV Cure research at this time, here are four global trends that will direct the path toward HIV research in the U.S. through 2025.

1. Funding is tight

The entire world is focused on the pandemic, which has limited the availability of funds to pursue other diseases. From private foundations to governments around the globe, money is being spent on developing a vaccine and a cure for this terrifying virus. The World Economic Forum recently reported on a study conducted by the National Association for Business Economics (NABE). The NABE is the largest international association of professionals committed to the application of economics. They found that 80% of economists surveyed expected there was at least a 25% chance of a second economic downturn. Almost half said they didn’t expect U.S. GDP to completely rebound until at least the second half of 2022. Until the economy recovers, funding will remain tight.

2. The U.S. government is not focused on a cure

At his 2019 State of the Union address, President Trump announced the new “Ending the HIV Epidemic” plan. This 10-year initiative was launched by the U.S. Department of Health and Human Services (HHS) in 2020. It is intended to reduce new HIV infections by 90%, to less than 3,000 per year, by 2030. The HHS Office of the Assistant Secretary for Health will coordinate the work by collaborating agencies that include the CDC and NIH, among others. The AHEAD Dashboard provides data on the focus areas for the plan.  While laudable, this goal calls for the prevention of new infections, rather than the eradication of existing HIV/AIDS infections.

Image: www.HIV.gov

3. Traditional pharma is not focused on a cure

An August 17 recap of the current clinical trials for an HIV Cure compiled by the Treatment Action Group (TAG) using data sourced from clinicaltrials.gov indicates that the trials are sponsored by organizations other than pharmaceutical companies. One such company is ViiV Healthcare. They are working to improve and widen access to current antiretroviral therapies (ARTs). For the 1.1 million people in the U.S. living with HIV, as well as those around the world, this is an improvement but not a cure.

4. Biotech companies are focused on a cure

The TAG recap also gives evidence of a trend in the search for an HIV cure. The companies investing in the clinical trials for an HIV cure are biotech companies. These companies do not have antiretrovirals in their product line and are pursuing a cure instead. One area of interest is a vaccine to immunize people against HIV in the first place. Another is a functional cure in which the virus in a patient is inactivated and also cannot infect anyone else.

Vaccine for prevention: The NIH is investigating multiple approaches to prevent HIV. The NIAID currently has two late-stage, multinational vaccine clinical trials in process. These are known as Imbokodo and Mosaico.

Cell and gene therapy for a functional cure: On August 11, 2020, biotech company American Gene Technologies (AGT) announced clearance by the FDA to begin Phase 1 of the first human clinical trial for AGT’s lead HIV program. AGT will conduct its Phase 1 study at clinical sites in the Baltimore/D.C. area. AGT expects that these sites will begin enrollment in the Fall of 2020.

AGT CEO Jeff Galvin says, “We see that the suffering hasn’t ended at all, but the general public is not aware of the difficulties HIV+ individuals face with lifelong antiretroviral therapy and the psychological stress and stigma of HIV-infection.”

image: NIAID

In Closing

The next five years will be important ones for HIV cure research. Biopharma firms such as AGT will continue to take the lead in moving beyond life-extending treatment to a functional HIV cure. By 2025, researchers will be much further in their understanding of gene and cell therapies and their use in creating an HIV cure.

Published on AGT

When reports of a new immune deficiency disease hit the news in the summer and fall of 1981, the cause and method of transmission were unknown. At first, it seemed this new disease only affected gay men and, as a result, what is now known as HIV/AIDS was viewed by many as the consequence of a gay lifestyle. Researchers soon found that the HIV virus was a sexually transmitted disease that could infect partners of either gender. When experience showed that the virus could also be transmitted through organ donations and the blood transfusions those with hemophilia needed to survive, the public reacted with fear. They insisted that people who were infected be kept away from those who were not. The federal government passed legislation that protected the rights of those infected with HIV. The U.S. government also invested in HIV cure research, as did private individuals.

The CDC announced the major routes of transmission for HIV in 1984. The cause of the virus was identified the following year. By 1996, a “cocktail” of drugs that halted the progression of the HIV virus before it developed into AIDS was being used to treat patients. These antiretrovirals prolong life, but they are not a cure. To date, AIDS has taken more than 30 million lives worldwide. As AGT begins its trial for a cure for HIV/AIDS, here’s a closer look at the history of HIV cure research from the first days of HIV to the development of the antiretrovirals in use today.

Sounding the Alarm

The CDC announced the major routes of transmission for HIV in 1984. The cause of the virus was identified the following year. By 1996, a “cocktail” of drugs that halted the progression of the HIV virus before it developed into AIDS was being used to treat patients. These antiretrovirals prolong life, but they are not a cure. To date, AIDS has taken more than 30 million lives worldwide. As AGT begins its trial for a cure for HIV/AIDS, here’s a closer look at the history of HIV cure research from the first days of HIV to the development of the antiretrovirals in use today.

The L.A. Times and the San Francisco Chronicle immediately ran stories about the report. Within days, the CDC was notified of PCP (Pneumocystis carinii pneumonia) and other opportunistic infections, such as the rare and unusually aggressive cancer, Kaposi’s Sarcoma (KS), among groups of gay men in New York and California.

The CDC formed the Task Force on Kaposi’s Sarcoma and Other Opportunistic Infections just three days after publication of the initial MMWR. The job of the Task Force was to identify risk factors for PCP and KS and develop a case definition for use across the country.

On July 3, the MMWR reported KS and PCP among 26 gay men in New York and California. The New York Times published an article, “Rare Cancer Seen in 41 Homosexuals,” on the same day.

Discovering the Cause

By September 1981, the first Kaposi’s Sarcoma clinic opened in San Francisco as the number of reported cases in the U.S. climbed. It was assumed this new disease was limited to gay men until the first of those with hemophilia became infected through the blood supply. By the end of the year, there would be a total of 159 cases reported to date in the U.S.

By the Spring of 1982, it was estimated that tens of thousands of people might be affected by the new disease. The uncertainty over what caused this “Gay Cancer” and how it spread was a source of great anxiety for the public. On September 24, 1982, two significant events took place: the CDC defined and used the term AIDS (Acquired Immune Deficiency Syndrome) for the first time and Congress allocated $5 million to CDC for surveillance, with another $10 million allocated to the National Institutes of Health (NIH) for AIDS research.

By the end of the year, there would be 771 cases reported to date in the U.S. with 618 deaths.

Congress Passes Funding Bill

On March 4, 1983, the MMWR suggested that a sexually transmitted agent or exposure to blood or blood products might cause AIDS. In May, the U.S. Congress passed the first bill that included specific funding for AIDS research and treatment. Agencies within the Department of Health and Human Services received $12 million. That same month, the Pasteur Institute in France reported the discovery of a retrovirus (LAV) that could be the cause of AIDS.

On September 9, 1983, the CDC MMWR identified all major routes of HIV transmission. The MMWR also ruled out transmission by casual contact, food, water, air, or surfaces. This information was comforting to the public. However, it did not alter the public’s fear of interaction with those who were infected. Realizing this, AIDS organizations pushed hard for a series of legal protections. In response to the global spread of HIV/AIDS, the World Health Organization (WHO) began international surveillance of the disease that November. Research into potential treatments for HIV/AIDS was taking place on a global scale.

By the end of the year, there would be 2,807 reported cases to date in the U.S. with 2,118 deaths.

Search for a Cure

Antiretrovirals

The first step in the search for an HIV cure was to identify the specific cause of HIV. By April of 1984, less than four years from the first reports of this new disease, HHS Secretary Margaret Heckler announced that Dr. Robert Gallo and his colleagues at the National Cancer Institute had identified a retrovirus, labeled HTLV-III, as the cause of AIDS. In conjunction with this finding, Heckler announced that a diagnostic blood test had been developed. It was now possible to test for HIV and inform those afflicted, but there was still no hope for long-term survival from this horrific disease.

By the end of the year, there would be 7,239 cases reported to date in the U.S. with 5,596 deaths

Many researchers focused on finding a way to keep the virus (HIV) from developing into full-blown disease (AIDS). They reasoned that this approach would prolong the life of those with the virus.

By the end of 1986, in the U.S. there had been 28,712 cases of AIDS reported to date with 24,559 deaths and there was intense pressure from the arts and gay communities to find a workable treatment. In 1987, the AIDS Clinical Trials Group (ACTG), one of the largest HIV clinical trial organizations in the world, was founded to broaden the scope of the HIV Cure research efforts at the NIH. One of the first drugs they worked on as a way to halt HIV was AZT (azidothymidine), a drug initially developed to treat cancer. Researchers recognized that, while this antiretroviral could stop the progression of HIV, the use of a single drug would not do the trick because its efficacy diminished over time. By the end of 1988, the U.S. had 82,362 cases of AIDS reported to date with 61,816 deaths.

In 1988, the Assistant Secretary for Health established the Office of AIDS Research (OAR), later codified into law, to provide increased coordination of efforts to defeat HIV/AIDS. 1988 also saw the first World AIDS Day bring attention to the role of “civil society” in mobilizing a global response to this global disease. By the end of 1989, there had been 117,508 cases of AIDS reported in the US with 89,343 deaths.

Effective Treatment but No Cure

In 1993, Congress passed the NIH Revitalization Act. This Act authorized OAR to:

• plan, coordinate, and evaluate HIV/AIDS research; 
• set scientific priorities for the NIH research agenda; and 
• determine budgets for all NIH HIV/AIDS research.

Despite the Act, the number of reported cases and deaths in the US and worldwide continued to rise as work on a more effective treatment or HIV cure continued. In 1996, researchers found that triple-drug therapy could suppress HIV long-term without loss of effectiveness. The number of Americans dying from AIDS dropped for the first time with a 23% decrease from 1995. The drop was attributed to the new antiretroviral treatment.

Internationally, the number of reported AIDS cases continued to soar. By 1999, the HIV infection rate had doubled since 1996 in over 27 countries. More than 95% of all of those infected with HIV lived in the developing world. Of the total deaths due to AIDS, 95% to date occurred in those nations. The lack of access to antiretrovirals spurs UNAIDS and the World Health Organization (WHO) to initiate the ‘3 by 5’ Initiative to provide antiretroviral treatment to 3 million people worldwide by the year 2005.

In 2004, the year AIDS-related deaths hit their peak, the United Nations reported a growing AIDS crisis in Eastern Europe and the former Soviet Union. It was reported that 15 million children worldwide have lost one or both parents to HIV/AIDS. In the U.S., there had been 940,000 cases of AIDS reported to date with 529,113 deaths. In 2005, WHO and UNAIDS released a report showing that the number of people on HIV antiretroviral drugs in developing nations had more than tripled to 1.3 million since 2003. In 2007, UNAIDS initiated new surveillance methods and estimated that 33 million people worldwide were living with HIV/AIDS. More than 25 years of coordinated global effort had produced an effective treatment, yet there was still no HIV cure.

Clinical Trial for an HIV Cure 

One of the promising developments in the search for an HIV cure is AGT’s Phase 1 clinical trial to investigate the safety of AGT103-T, a single-dose, lentiviral vector-based gene therapy developed to eliminate HIV from the millions of people globally infected with the disease. AGT is dedicated to finding a functional HIV cure because, with the use of antiretrovirals, CEO Jeff Galvin says, “we see that the suffering hasn’t ended at all. It’s just gone underground. You can have a relatively normal lifespan, but they have actually just shown statistically that your lifespan is shorter. Your quality of life is also significantly lower. And the psychological impact of the whole thing essentially makes you feel like you have a life sentence that you’re serving. Science moved it from a death sentence to a life sentence. But what we want to do is get these people ‘out of jail’ and truly free from the impact of their infections.”

Sources

International

Avert Global Info and Education on HIV and AIDS

amfAR HIV/AIDS: Snapshots of an Epidemic – reported cases

UNAIDS Global HIV/AIDS Statistics 2020 Fact Sheet

WHO HIV/AIDS

U.S.

AIDS.gov Timeline of HIV/AIDS

CDC About HIV

CDC NPIN HIV Illustrated Timeline

HIV.gov Timeline of AIDS

NIH Office of AIDS Research

HIV Historical Timeline

Published on AGT