World AIDS Day: A Look Back at the Puzzle

Several days ago, I was working on a puzzle with my two boys. My oldest is a meticulous artist. He is attuned to colors and lines, small details, and shapes. My youngest is my large motor kid: attuned to the big picture and huge body movements. They come from a long line of athletes and artists who each encompassed the skills I now find in my boys. 

My favorite family artist is/was my Uncle Mike. He passed when I was the same age as my youngest. His art hangs on the walls of every member of my family, as well as all over my home. Like my oldest, Uncle Mike was attuned to lines and color and the spaces he observed. Like my youngest, his strokes were broad and large, with a big picture always in mind. 

Every year on World AIDS Day, our family reflects on the life and subsequent death of my Uncle Mike.  We celebrate his life, mourn his early passing, and discuss his art as a piece of the legacy he left behind.  Our family’s story is one small piece of the HIV/AIDS epidemic puzzle. Uncle Mike is just one loss caused by the horrible infection that still carries a negative stigma today. As a family, we have worked to support HIV/AIDS causes, shared our story, and celebrated the advances in medical discoveries that continue to add to the scaffolding of knowledge of the virus that has affected so many.

In terms of medical discoveries, TJ Cradick, PhD, was and is a essential piece of the HIV/AIDS puzzle. Dr. Cradick has been a member of ASGCT since 2005 and is highly regarded in the world of gene editing and HIV/AIDS research.

When Dr. Cradick began his work in Cambridge, Mass., on HIV therapeutics at Repligen, they were sequencing HIV and developing exciting monoclonal antibody approaches that looked promising in primate models. Repligen was also involved in early cell therapy work.

It was those discoveries that were part of the puzzle pieces that led to better medicine for individuals living with HIV/AIDS. During this time, my family was in San Francisco, taking care of Uncle Mike and saying goodbye. Our family’s big picture was forever changed, and the sciences were as well.

Dr. Cradick then joined Matthias Wabl's lab at UCSF to develop methods to select for proteolytic antibodies targeting HIV. During his time at UCSF, Dr. Cradick had a pharmacist roommate who described dispensing large boxes of AZT and other medications to people living with HIV. There was an urgency to make discoveries—individuals’ lives were at risk; people were dying; and their stories and their friends and family’s losses were adding to the puzzle, providing a larger, much more painful picture of the disease.

Dr. Cradick joined Sangamo Biosciences (now Sangamo Therapeutics) designing and selecting Zinc Finger proteins and then Zinc Finger Nucleases (ZFNs). Sangamo greatly advanced the field of gene editing with their work on ZFNs, including ZFNs that knocked out CCR5, an HIV co-receptor, which resulted in T cells that were resistant to HIV infection. The seminal work establishing gene editing increased the possibility of future treatments that could slow or stop the progression of HIV/AIDS and other diseases.

While Dr. Cradick was working on the meticulous and smallest detailed puzzle pieces of HIV/AIDS, my family was using the momentum of loss to partner with the AIDS Resource Center of Wisconsin, at that time called the Milwaukee AIDS Project (MAP). Every Monday, I vividly remember packing up in my mom’s Volkswagen Vanagon, collecting meals and food from local churches and organizations to take down to MAP. This volunteer work was deeply important to my family and became a part of who I was.

Despite the many advances in the HIV/AIDS sciences through Dr. Cradick and many others’ diligent work, there were many family and friends who were lost to the disease. While further understanding of the disease and better treatments were becoming more available, the stigma of the disease was still another piece of the puzzle that affected so many people living with HIV and their loved ones. Even years after his death, Uncle Mike’s story stayed within our family home; little was shared for fear of that stigma.

After moving to a faculty position at Georgia Tech, Dr. Cradick's research continued on ZFNs and TAL effector nucleases (TALENs). Starting in 2012, Dr. Cradick's group began work on CRISPR nucleases. Working with Gang Bao’s lab and other collaborators, their group co-published early papers on CRISPR specificity, including characterizing nucleases targeting CCR5 and nucleases targeting near the sickle cell mutation. Similar strategies continue to be developed by a number of groups targeting the HIV co-receptor or developing therapeutics for Sickle Cell disease or Beta thalassemia.

Dr. Cradick joined CRIPSR Therapeutics as the second U.S. employee and Head of Genome Editing. Early work focused on hemoglobinopathies, leading to the ongoing clinical trial for CTX-001 and expanding their gene editing technologies.

Dr. Cradick’s CRISPR research continues at Excision BioTherapeutics, a company committed to developing CRISPR-based therapies to cure viral infectious diseases that address unmet medical needs. Dr. Cradick described how their virologists and bioinformaticians collaborate to build better viral databases and work with the gene editing scientists to develop methods to improve viral inactivation.

Excision and collaborators developed EBT-101, which uses CRISPR-Cas9 to target three sites within integrated HIV, allowing three possible inactivating deletions. EBT-101 is designed to cure HIV infections after a single infusion. Dr Cradick described how the EBT-101 Phase 1/2 trial for HIV will provide valuable information on the path to a potential functional cure for people living with HIV. 

EBT-101 addresses an area of high unmet need as there are no curative treatments for HIV, and current chronic treatment options are expensive and lead to significant side effects. Excision BioTherapeutics announced dosing the first patient in September 2022 in the Phase 1/ 2 trial evaluating EBT-101 as a potential cure for HIV. Dr. Cradick expressed excitement that, due to Excision’s exclusive focus on targeting virus, technologies developed for the HIV program will aid the company’s efforts to target other viruses with large patient populations and high unmet medical need, including Hepatitis B virus (HBV) and Herpes simplex viruses (HSV).

Today, the HIV/AIDS puzzle has many more pieces in place but is not yet complete. The medical discoveries and current therapies and treatment for individuals living with HIV have increased life spans and allowed for significantly healthier outcomes. There is less stigma attached to those who are living with and those who have passed from the disease. In my own extended family, we have just begun to process Uncle Mike’s diagnosis and death together with open dialogue. Much of the healing from the untimely loss was done individually, quietly. However, as new therapies and technologies are developed by doctors and scientist like Dr. Cradick, the stigma lessens, allowing others to share their stories more freely.

When the opportunity came to interview Dr. TJ Cradick, I was excited to highlight his extensive work. I was emotional to speak with someone whose mind and discoveries have quietly shaped so many lives. This was a full circle moment for me, where the pieces of my own puzzle about HIV found the connection with someone else’s.

As we talked, I found similar themes: hope for a cure, the emotional and medical burden is placed on individuals with the disease and their loved ones, and how each experience or discovery builds to more understanding. Just like when my boys and I are doing a puzzle, we all must come to the table to work together to get the entire picture. There is always a celebratory “YES!” when pieces and chunks are pulled together.

I end with this: 20 years ago, I never envisioned myself working outside the classroom but have since transitioned to the opportunity to work on the diversity, equity, and inclusion (DEI) initiatives at ASGCT to raise awareness. Through this role I am tasked with raising awareness for many underrepresented and under supported groups working in and impacted by gene and cell therapies.

It humbles me to raise awareness for a cause close to home by sharing my family’s story about Uncle Mike and having discussions with cutting edge HIV/AIDS scientists. I am so very grateful for the incredible work of these scientists and clinicians and the bravery of those living with the disease. On this World AIDS Day, my puzzle is just that more complete.   

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