Investigate the treatment, management and possible future directions for the cure of non-infectious diseases through pharmaceutical intervention, gene therapy and lifestyle change

What this dot point is asking

NESA wants you to describe how non-infectious diseases are managed and possibly cured through pharmaceutical intervention, gene therapy and lifestyle change, with named examples and an honest evaluation of strengths and limits.

The answer

Treatment of non-infectious disease operates on three fronts: pharmaceutical (drugs that modify physiology), gene therapy (correction of the underlying genetic defect) and lifestyle change (behavioural modification of risk factors). Most chronic disease is managed by a combination of all three.

Pharmaceutical intervention

Pharmaceuticals modify physiology by targeting receptors, enzymes, transporters or ion channels. They are the workhorse of chronic disease management.

Hormone replacement.

• Insulin (recombinant human insulin since 1982) is essential for type 1 diabetes and used in advanced type 2 diabetes. Delivered by injection or insulin pump.
• Thyroxine (levothyroxine) replaces thyroid hormone in hypothyroidism.

Diabetes drugs.

• Metformin. First-line in type 2 diabetes. Reduces hepatic glucose output and improves insulin sensitivity.
• SGLT2 inhibitors (empagliflozin, dapagliflozin). Block glucose reabsorption in the kidney; also reduce cardiovascular events and slow kidney disease.
• GLP-1 receptor agonists (semaglutide). Stimulate insulin release and suppress appetite. Produces 10 to 15 percent weight loss; reduces cardiovascular events.

Cardiovascular drugs.

• Statins. Inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Lower LDL by 30 to 50 percent and reduce heart attack and stroke risk by approximately a quarter.
• Antihypertensives. ACE inhibitors, ARBs, beta blockers, calcium channel blockers and diuretics all lower blood pressure by different mechanisms.
• Antiplatelets and anticoagulants. Aspirin (irreversibly inhibits cyclooxygenase in platelets), clopidogrel, warfarin, direct oral anticoagulants (apixaban, rivaroxaban).

Targeted molecular therapies.

• CFTR modulators (ivacaftor, elexacaftor/tezacaftor/ivacaftor) bind the CFTR protein and restore its function in cystic fibrosis patients with specific mutations. Have transformed CF prognosis since 2012.
• Monoclonal antibodies. Trastuzumab targets HER2 in breast cancer; pembrolizumab is an immune checkpoint inhibitor used across multiple cancers.

Cancer chemotherapy. Cytotoxic agents (cisplatin, doxorubicin, paclitaxel) damage rapidly dividing cells; selective for cancer but with collateral toxicity to bone marrow, gut and hair follicles.

Gene therapy

Gene therapy modifies the patient's DNA to correct a genetic defect. Two main approaches:

Gene addition. A functional gene is delivered to the patient's cells, usually by a viral vector (adeno-associated virus, lentivirus).

• Luxturna (voretigene neparvovec). Approved 2017. Treats Leber congenital amaurosis caused by RPE65 mutations. A functional RPE65 gene is delivered to retinal pigment epithelial cells by AAV injection under the retina, partially restoring vision.
• Zolgensma. Approved 2019. Treats spinal muscular atrophy by AAV-delivered SMN1 gene. Single infusion in infancy can prevent lethal motor neuron loss.

Gene editing (CRISPR-Cas9). Cas9 nuclease guided by a short RNA precisely cuts a chosen DNA sequence, which the cell repairs through homology-directed repair (introducing a correct sequence) or non-homologous end joining (disabling a gene).

• Casgevy (exa-cel). Approved 2023. Treats sickle cell disease and beta-thalassaemia by editing BCL11A in patient bone marrow stem cells to reactivate fetal haemoglobin. Patients in trials are crisis-free.

Strengths. Potentially curative; targets root cause; one-time treatment.

Limitations. Cost (Casgevy approximately 3 million Australian dollars per patient); access (specialist centres only); off-target editing risk; ethical concerns around germline editing.

Lifestyle change

Lifestyle interventions modify behavioural risk factors and often work on multiple diseases at once.

Diet.

• Mediterranean diet (vegetables, legumes, whole grains, olive oil, fish, modest wine) reduces cardiovascular events by approximately 30 percent in trials (PREDIMED, 2013).
• DASH diet (Dietary Approaches to Stop Hypertension) lowers blood pressure by 8 to 14 mm Hg.
• Low-glycaemic and reduced-energy diets improve glycaemic control in type 2 diabetes; 5 to 10 percent weight loss can induce remission.

Physical activity

150 minutes of moderate aerobic activity plus 2 sessions of resistance training per week reduces cardiovascular mortality by approximately 30 percent, improves insulin sensitivity, and reduces depression and dementia risk.

Smoking cessation

Halves the excess cardiovascular risk within 1 year; lung cancer risk approaches non-smoker rates after 15 to 20 years.

Alcohol reduction

Australian guidelines recommend no more than 10 standard drinks per week. Reduction reduces hypertension, atrial fibrillation, liver disease and several cancers.

Sleep and stress

Chronic sleep deprivation and unmanaged stress contribute to hypertension, insulin resistance and depression. Cognitive behavioural therapy is effective for both.

Comparing the three approaches

In practice these are layered: a person with type 2 diabetes might use metformin (pharmaceutical), Mediterranean diet and exercise (lifestyle), and, in the future, possibly gene editing of metabolic regulators (gene therapy).

Future directions

• CRISPR base editing and prime editing. Edit single bases without double-strand breaks, reducing off-target damage.
• In vivo CRISPR. Editing inside the body rather than ex vivo, reducing cost and complexity.
• mRNA therapeutics. Beyond vaccines, mRNA is being trialled for cancer (personalised neoantigen vaccines) and protein replacement.
• Polygenic risk scores. Use whole-genome sequencing to identify high-risk individuals before disease develops.
• AI-guided drug design. Models such as AlphaFold accelerate the identification of new drug targets.
• Microbiome modulation. Faecal microbiota transplant and engineered probiotics for inflammatory and metabolic disease.

Examples in context

Example 1. Trikafta (elexacaftor/tezacaftor/ivacaftor) for cystic fibrosis in Australia. Listed on the PBS in April 2022, Trikafta is a triple-combination small-molecule drug that corrects the F508del CFTR mutation underlying around 70 percent of cystic fibrosis cases. The three drugs work together: elexacaftor and tezacaftor act as "correctors" that help misfolded CFTR protein reach the cell membrane, while ivacaftor is a "potentiator" that opens the chloride channel once it arrives. Lung function (FEV1) improves by an average 14 percent within weeks of starting therapy, and pulmonary exacerbations drop by 63 percent. Sydney Children's Hospital cystic fibrosis clinics estimate that around 1500 Australian patients are now on Trikafta, transforming what was a paediatric-only disease into a manageable adult condition.

Example 2. Lifestyle intervention reverses early type 2 diabetes. The Diabetes Remission Clinical Trial (DiRECT), with results published in 2018 and replicated in Australian primary care contexts since, showed that a structured very-low-calorie diet of 800 kcal per day for 12 weeks followed by weight maintenance achieved remission of type 2 diabetes in 46 percent of recently diagnosed patients (within 6 years of diagnosis). Remission was sustained at 2 years in over a third. The mechanism is fat loss from the pancreas and liver, restoring insulin sensitivity. NSW Health endocrinology clinics now routinely offer Type 2 Diabetes Reversal programs alongside metformin and insulin. This is a striking example where lifestyle alone, supervised intensively, outperforms pharmaceutical-only management for selected patients.

Try this

Q1. Distinguish between somatic gene therapy and pharmaceutical intervention for treating a genetic disease. [3 marks]

• Cue. Somatic gene therapy corrects the underlying mutation in patient body cells (potentially curative for one patient); pharmaceuticals manage symptoms or compensate for the missing protein but must be taken continuously.

Q2. A clinical trial of a new statin reports LDL cholesterol falling from 5.2 mmol/L to 2.9 mmol/L over 12 weeks in 300 patients. Calculate the average reduction and explain why this may not translate to reduced cardiovascular events. [3 marks]

• Cue. Reduction of 2.3 mmol/L (44 percent). Surrogate endpoints (LDL) do not always translate to clinical endpoints (MI, stroke); cardiovascular risk depends on many factors.

Q3. Evaluate the role of gene therapy in treating genetic disease. (a) Identify one approved gene therapy and the disease it treats. (b) Identify one major limitation. (c) Justify whether gene therapy will replace pharmaceutical management in the next decade. [2+2+3 marks]

• Cue. (a) Luxturna for RPE65 inherited blindness, or Casgevy for sickle cell. (b) Cost (1 to 4 million AUD per patient), availability, off-target effects, durability of correction. (c) A reasoned judgement: replacement unlikely soon due to cost; complementary roles likely.