How we can bring gene therapies to bear on diseases of aging

This article is part of a series about challenges and opportunities in developing treatments for Alzheimer’s and Dementia.

Like many others, I have lost family members to illnesses of aging, including dementia and cancer. I know first-hand the emotional and financial burden of diseases that strike in the final decade or two of life. For all the patients who struggle with the toll of age-related diseases, gene therapies offer a ray of hope. 

The first generation of gene therapies primarily focused on rare pediatric diseases and delivered significant clinical benefits. Next-generation gene editing technologies may allow drug developers to broaden their offerings to the unmet needs of older patients. Changes in a single gene or multiple genes often initiate the progression of age-related diseases, making them ideal targets.1  Intractable central nervous system (CNS) disorders of aging such as dementia, Alzheimer’s, and Parkinson’s disease are now in the crosshairs, meaning more patients may get access to life-altering treatments.

Older patients are (still) routinely excluded from clinical trials

The pandemic revealed inequities in clinical research. Among them, direct and indirect exclusions resulted in fewer adults over 65 enrolling in studies of potentially lifesaving COVID-19 vaccines and treatments. One review of eligibility criteria for clinical studies initiated in 2019 found they excluded older adults from more than 50 percent of treatment and 100 percent of vaccine trials.2 Yet COVID-19 caused disproportionate illness and death in this age group. Under-enrolling a critical target patient segment renders trial results less valid, generalizable, and informative.

Randomized controlled trials (RCTs) often exclude people who:

  • Have prevalent age-related conditions such as high blood pressure, heart disease, mild cognitive dysfunction, and diabetes;
  • Take concomitant medications such as blood thinners and beta-blockers;
  • Face transportation or technological challenges due to aging, such as being less mobile or proficient with mobile devices and apps;
  • Suffer a higher incidence of drug-related adverse events or an altered efficacy and safety profile due to the pharmacokinetics of aging and 
  • Have mental or functional limitations that may compromise the informed consent process.

Overly strict eligibility criteria can result in clinical trials that routinely enroll younger- and healthier-than-average participants, unlike most geriatric patients.3 This is wrong and would never be permitted against other demographic groups. We must test new treatments on the patients who need them: the scientific, ethical, and financial consequences of continuing to under-represent older patients in clinical research will become intolerable for families, businesses, and society.

How can we restore equity for the new era of gene editing?

As a scientist and business executive, I understand that the desire for “clean” data leads sponsors and regulators to focus on patients without complex comorbidities and polypharmacy in trials. However, this priority can get in the way of helping real-life patients.

The industry is understandably risk-averse; we must worry about the dangers of off-target genome editing for newer gene therapies in all populations. Yet, we are making progress; on October 31, 2023, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) considered the safety profile of Vertex Pharmaceuticals’ and CRISPR Therapeutics’ sickle-cell disease therapy Casgevy (exagamglogene autotemcel) and concluded it is safe enough for human use.4 It became the first gene-editing product ever approved by the FDA on December 8.5 The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) was the first to license Casgevy on November 15, 2023.6 

Casgevy requires a grueling treatment regimen that includes blood transfusions, chemotherapy, and hospitalization; many elderly patients would not be able to tolerate it. Nevertheless, gene-editing technologies will advance and may evolve to point-of-care delivery. We should not write off testing this promising new class of drugs in older adults. Here are some practical approaches we can adopt to improve the chances of enrolling older patients.

1. Reject ageism in thought and trial design

Clinical research aims to find treatments for unmet medical needs, whether those needs exist for a four-year-old or an 80-year-old. Neither of these patients is more valuable or suffers more acutely than the other. Both are fragile and require heightened safeguards and unique accommodations in clinical trial design. We can work to develop drugs for both.

Clinical trials have historically underrepresented older people in part because of implicit and explicit ageism ingrained in our healthcare system and attitudes. A recent editorial noted that even the greeting card section of your local drugstore depicts aging as a process that inevitably leads to functional and cognitive decline.7

Likewise, a systematic review of 149 healthcare access studies found that in 85% of them, providers offered more procedures and treatments to younger patients than to older patients, even if they could benefit both.8

Is it easy to design trials that accommodate 80-year-old patients? No. Developing treatments for older adults presents unusual challenges and demands a concerted effort to understand the patient experience and include the patient’s voice throughout the development lifecycle. Can that be done? Yes.

2. Recruit representative patients starting in Phase 1

At Parexel, we work with many sponsors developing drugs for Alzheimer’s disease (AD), but we noticed that inclusion/exclusion criteria tended to select younger patients, especially in Phase 1 trials.

To address the problem, we designed a memory clinic within our Early Phase Clinical Pharmacology Unit (EPCU) in Los Angeles. The clinic provides cognitive and biomarker testing as standard procedures for all healthy volunteers over 60. Blood biomarkers are an imperfect tool (at least for now), but they can help identify and stratify apparently normal older persons who may be at risk for AD.

We aim to build a database of experienced early-phase research participants to boost recruitment into early-phase AD trials. By providing resources and education to patients, their treating physicians, and caregivers in the community, the memory clinic improved recruitment significantly for our Phase 1 unit.9

3. Use advanced analytics to reexamine eligibility criteria

Unless and until regulators and sponsors find a scientifically valid way to include a more “medically diverse” pool of patients in clinical trials, many middle-aged and elderly patients will lack access to cutting-edge therapies.

We must enroll patients with prevalent comorbidities such as obesity, diabetes, and heart disease, who are taking concomitant meds, and those with mental or functional limitations. How can we achieve this?

We recently helped a client predict the relevance of a drug-drug interaction (DDI) using physiologically based pharmacokinetic (PBPK) modeling. Such analytics offer a route to allowing more concomitant medications without running time-consuming DDI studies. Our modeling and simulation experts reviewed the preclinical in vivo and in vitro data and the first-in-human clinical data to investigate the allowed concomitant medications for the client’s Phase 2 trial. The results suggested that inhibitors of the relevant metabolic pathway did not impact the exposure of the drug because other metabolic pathways could compensate. However, it confirmed that enzyme-inducer medications could reduce the drug’s exposure, affecting efficacy. With this knowledge, the sponsor broadened the criteria for concomitant medications for its Phase 2 trial. Our PBPK analysis took three months, requiring far less time and money than a DDI trial.

4. Utilize blood tests to stratify patients precisely

A recent study showed promise for a two-step, cost-effective blood test that uses plasma p-tau217 levels to stratify AD risk for patients with mild cognitive impairment.10 Proactive genetic screening for brain diseases is increasing, yielding new epidemiological insights and biomarker information.11 These advances are significant because few effective treatments exist for many CNS conditions that are increasingly diagnosed in people in their 50s and 60s12 and bring high socioeconomic and personal costs. Suppose accurate tests could stratify patients by risk. In that case, it may be easier to design multi-cohort trials that enroll patients with comorbidities and generate scientifically valid proof of efficacy and safety.

A call to action 

We have a generation in their 60s and 70s caring for parents in their 80s and 90s. If we can develop gene therapies to improve the quality of life and reduce healthcare resource utilization for these demographics, we should. But first, we need to reset our biases about enrolling patients 65 and older in clinical trials.

Learn more about Parexel’s comprehensive and cross-disciplinary Cell and Gene Therapy Center of Excellence here.



1 Gene Therapy Strategies Targeting Aging-Related Diseases (Aging and Disease, April 2023).

2 The Exclusion of Older Persons from Vaccine and Treatment Trials for Coronavirus Disease 2019—Missing the Target (JAMA Internal Medicine, November 2020). 

3 Clinical trials in older people (Age and Aging, May 2022).

4 Panel Says That Innovative Sickle Cell Cure is Safe Enough for Patients (The New York Times, October 2023).

5 FDA Approves First Gene Therapies to Treat Patients With Sickle Cell Disease (FDA Press Release, 2023).

6 MHRA authorizes world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia (Medicines and Healthcare products Regulatory Agency press release, November 2023).

7 Ageism as a barrier to eliciting what matters: A call for multigenerational action to confront the invisible “ism” (Journal of the American Geriatrics Society, August 2023).

8 Ageism is a global health challenge: UN (World Health Organization, March 2021)

9 Implementing a Memory Clinic Model to Facilitate Recruitment into Early Phase Clinical Trials for Mild Cognitive Impairment and Alzheimer’s Disease (The Journal of Prevention of Alzheimer’s Disease, February 2019).

10 A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases (Nature Aging, August 2023).

11 Perceptions of Knowledge, Disease Impact and Predictive Genetic Testing in Family Members at Risk to Develop Early-Onset Alzheimer’s Disease (EOAD) and Their Levels of Suicidal Ideation: A Mixed Study (Brain Sciences, March 2023).

12 Global Prevalence of Young-Onset Dementia (JAMA Neurology, July 2021).

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