What drugs are used to treat genetic conditions?

Drugs for Genetic Conditions

Drugs used to treat genetic conditions fall into three main categories: gene-targeted therapies that directly address the underlying genetic defect, pharmacogenetic-guided medications that require genetic testing for safe and effective use, and supportive therapies for managing symptoms of genetic diseases.

Gene-Targeted Therapies

Antisense Oligonucleotides (ASOs)

• ASOs represent a versatile genetic therapy platform with over 20 FDA-approved oligonucleotide therapies available for general applications 1
• These therapies can be customized to target specific genetic variants, even for individual patients (n=1 treatments) 1
• ASOs work through four main mechanisms: (1) downregulating transcripts in toxic gain-of-function variants, (2) restoring reading frames in truncating variants, (3) correcting aberrant splicing, and (4) increasing wild-type protein expression in haploinsufficiency disorders 1
• Delivery routes include systemic (subcutaneous/intravenous), intrathecal (brain/spinal cord), intraocular (eye), and targeted delivery to liver and muscle via GalNAc and transferrin receptor targeting 1
• Treatment requires repeated administration every 1-4 months due to finite half-life, allowing dose optimization for individual patients 1

CFTR Modulators

• Ivacaftor is FDA-approved for cystic fibrosis and requires mandatory genetic testing before initiation 1
• The drug regulates CFTR channel activity and improves lung function in patients with specific CFTR variants 1
• Patients homozygous for F508del mutation (two copies) are non-responders and should receive alternative treatment 1
• Current guidelines identify 33 CFTR variants associated with drug efficacy, making pre-treatment genetic testing essential 1
• Approximately 85-90% of European ancestry individuals with cystic fibrosis carry at least one F508del variant 1

Bile Acid Replacement Therapy

• Cholic acid is approved for bile acid synthesis defects (BASD) as replacement therapy 1
• The mechanism involves preventing accumulation of hepatotoxic atypical bile acids and restoring bile acid homeostasis 1
• This therapy demonstrates high efficacy in restoring normal liver function in BASD patients 1

Pharmacogenetic-Guided Medications

Anticoagulants

• Warfarin dosing requires genetic testing for CYP2C9, VKORC1, and CYP4F2 variants according to CPIC guidelines 1
• These three genes account for 18%, 30%, and 11% respectively of warfarin dose variability in European ancestry individuals 1
• Genetic variants alter drug metabolism (CYP2C9), target enzyme activity (VKORC1), and vitamin K recycling (CYP4F2) 1
• Both low and high INR can be harmful given warfarin's narrow therapeutic range, making genetic testing critical for safety 1

Antiretroviral Agents

• HLA-B*57:01 testing is FDA-mandated before initiating abacavir-containing HIV treatment 1
• Abacavir causes immunologically-mediated hypersensitivity reactions in 3-5% of HLA-B*57:01 positive patients during the first 6 weeks 1
• The PREDICT-1 trial demonstrated that prospective screening eliminating HLA-B*57:01 positive patients from abacavir treatment reduced hypersensitivity reactions from 2.7% to 0% 1
• This represents a clear example where genetic testing prevents potentially fatal adverse events 1

CPIC Guidelines Framework

• The Clinical Pharmacogenetics Implementation Consortium has published 36 pharmacogenetic drug guidelines covering variants in 15 genes 1
• CPIC recommendations are based on randomized controlled trials and clinical studies, focusing on gene-drug pairs with CLIA-approved genetic tests 1
• Guidelines specify when to change drug dose or consider alternative drugs but do not mandate test ordering 1

Supportive Therapies for Genetic Cholestatic Diseases

Ursodeoxycholic Acid (UDCA)

• UDCA changes bile acid composition from hydrophobic to hydrophilic, reducing toxic bile acid accumulation 1
• Efficacy is low in FIC1 deficiency but variable (none to high) in MDR3 deficiency depending on genotype 1
• Used off-label for AATD, Alagille syndrome, and various PFIC subtypes 1

Rifampicin

• Acts through PXR activation resulting in bile acid detoxification 1
• Demonstrates moderate efficacy in decreasing cholestatic pruritus 1
• Used experimentally for Alagille syndrome, FIC1 deficiency, BSEP deficiency, and MDR3 deficiency 1

Cholestyramine

• Bile acid-binding resin that interrupts enterohepatic circulation 1
• Shows marginal efficacy for cholestatic pruritus 1
• Applied across multiple genetic cholestatic conditions 1

Critical Implementation Considerations

Genetic Testing Requirements

• Genetic testing must be performed before initiating ivacaftor (mandatory) and abacavir (FDA-recommended) to prevent treatment failure or life-threatening adverse events 1
• Warfarin genetic testing is recommended by CPIC to optimize dosing and prevent bleeding or thrombotic complications 1
• Testing availability exists for all CPIC-recommended gene-drug pairs through CLIA-approved laboratories 1

Common Pitfalls

• Not all genetic variants are amenable to ASO therapy; systematic assessment of variant eligibility is essential before pursuing this treatment approach 1
• The low penetrance of some genetic variants (e.g., APOL1 with only 20% developing disease) limits the utility of genetic testing for prognosis in certain conditions 1
• Pharmacogenetic testing is currently limited to few variants and drugs despite great interest in the field 1

Emerging Therapies

• Gene therapy products are rapidly expanding, with 5 FDA-approved gene therapies for rare Mendelian diseases as of 2022 and many more in development 1
• Next-generation sequencing and gene editing technologies are accelerating development of curative genetic therapies 2
• Approximately 6% of the world's population lives with a rare disease, but only 5% of 7,000 known rare diseases have approved disease-modifying treatments 1