Advancements in Gene Editing for Treating ATTR-CM

CardioNerds (Drs. Rick Ferraro and Georgia Vasilakis Tsatiris) discuss ATTR cardiac amyloidosis with expert Dr. Justin Grodin. This episode is a must-listen for all who want to know how to diagnose and treat ATTR with current available therapies, as well as management of concomitant diseases through a multidisciplinary approach. We take a deep dive into the importance of genetic testing, not only for patients and families, but also for gene-specific therapies on the horizon. Dr. Grodin draws us a roadmap, guiding us through new experimental therapies that may reverse the amyloidosis disease process once and for all.  Audio editing by CardioNerds academy intern, Christiana Dangas.

This episode was developed in collaboration with the American Society of Preventive Cardiology and supported by an educational grant from BridgeBio. 

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Pearls:

1. You must THINK about your patient having amyloid to recognize the pattern and make the diagnosis. Start with a routine ECG and TTE, and look for a disproportionately large heart muscle with relatively low voltages on the ECG. 

2. Before you diagnose ATTR amyloidosis, AL amyloidosis must be ruled out (or ruled in) with serum light chains, serum/urine immunofixation, and/or tissue biopsy. 

3. Genetic testing is standard of care for all patients and families with ATTR amyloidosis, and the future is promising for gene-specific treatments. Current FDA-approved treatments for TTR amyloidosis are TTR stabilizers and TTR silencers, but TTR fibril-depleting agents are on their way. 

4. Early diagnosis of ATTR affords patients maximal benefit from current amyloidosis therapies.  
5. TTR amyloidosis patients require a multidisciplinary approach for success, given the high number of concomitant diseases with cardiomyopathy. 

Notes:

Notes: Notes drafted by Dr. Georgia Vasilakis Tsatiris. 

1. What makes you most suspicious of a diagnosis of cardiac amyloidosis from the typical heart failure patient? 

You must have a strong index of suspicion, meaning you THINK that the patient could have cardiac amyloidosis, to consider it diagnostically. Some characteristics or “red flags” to not miss:  

• Disproportionately thick heart muscle with a relatively low voltages on EKG  

• Bilateral carpal tunnel syndrome – estimated that 1 in 10 people >65 years old will have amyloidosis  

• Previously tolerated antihypertensive medications 

• Atraumatic biceps tendon rupture  

• Bilateral carpal tunnel syndrome 

• Spinal stenosis  

• Concomitant with other diseases: HFpEF, low-flow low-gradient aortic stenosis 

2. How would you work up a patient for cardiac amyloidosis?  

• Start with a routine ECG (looking for disproportionally low voltage) and routine TTE (looking for thick heart muscle) 

• CBC, serum chemistries, hepatic function panel, NT proBNP, and troponin levels 

NOTE: It is critical to differentiate between amyloid light chain (AL amyloidosis) and transthyretin ATTR amyloidosis, as both make up 95-99% of amyloidosis cases.  

• Obtain serum free light chains, serum & urine electrophoresis, and serum & urine immunofixation to rule out AL amyloidosis. (See table below) 

3. What treatment options do we have to offer now for ATTR CM, and how has this compared to prior years?  

• Before 2019, treatment options were limited outside of cardiac transplantation and prophylactic liver transplants for hereditary ATTR amyloidosis. 

Treatments since 2019 have utilized the amyloidogenic cascade: 

• TTR protein is formed in the liver and circulates in the bloodstream.  

• Current treatments aim to either slow ATTR progression by stopping deposition or clearing amyloid deposits 

• Only FDA-approved treatments are for stopping deposition, while agents that clear amyloid deposits remain investigational. Two classes of agents that stop amyloid deposition are TTR stabilizers and TTR Silencers. (See table below) 

• Agents that clear amyloid deposits are still in clinical trials (ALXN2200, Coramitug PRX004). 

• Liver transplantation is the only method of clearing amyloid fibril deposits until the FDA approves a fibril-depleting agent, as perhaps one of the aforementioned agents.  

4. How do you use genetic testing in your practice? How does the role of genetic testing impact treatment options for patients and their families?  

• Genetic testing = standard of care; everyone with ATTR-CM should get genetic sequencing! 

• Family screening is also important, as hATTR is an autosomal dominant disease. Patients and families can be referred to genetic counseling, become educated on the GINA Act, and choose to start cascade screening for family members. 

• Family members can be affected in different ways, as penetrance can occur at different ages  

• Due to current FDA labeling patients must have hereditary ATTR with polyneuropathy and a pathologic variant to qualify for TTR silencer treatment. Patients can have concomitant cardiomyopathy but must also have polyneuropathy and pathologic variant.  

• TTR stabilizers are approved for ATTR cardiomyopathy regardless of the presence of the pathogenic TTR variant.  

5. Are there differences in treatment response between wtATTR or hATTR? What about differences in men and women? 

• Epidemiological studies suggest variant (hereditary) ATTR patients have more aggressive disease than wildtype ATTR patients.  

• Since current treatments do not cure the disease and work to slow progression, patients with advanced stages of disease do not show much benefit from current therapies. 

• Whether it is wild type or hereditary, diagnosing ATTR as early as possible will afford patients the greatest therapeutic impact of current treatments.  

• The current data does not suggest a therapeutic difference in response between men and women with ATTR cardiac amyloidosis 

6. What is the role of CRISPR/Cas9 in the treatment of cardiac amyloidosis?  

• ATTR amyloidosis is an elegant disease model because it is one gene responsible for one protein and ultimately one disease process. 

• NTLA 2001 (currently in a phase-three clinical trial, link to phase one) is an agent administered in a single infusion to silence hepatic production of TTR indefinitely. 

• We are awaiting promising results from this trial at the time of this recording. 

7. How can we best call on our friends in other subspecialities to take care of the concomitant diseases – peripheral neuropathy, symptomatic atrial fibrillation, aortic stenosis? Do any ATTR specific treatments show improvement in these manifestations? 

• TTR amyloidosis patients need a multidisciplinary care model for success. 

• Carpal tunnel syndrome is common in ATTR amyloidosis, so referrals to neurology and hand surgery are common 

• Patients with autonomic dysfunction secondary to autonomic neuropathy could benefit from neurology referral for blood pressure strategies and gastroenterology due to gut dysmotility and constipation. 

• Electrophysiology (EP) referral is common for atrial fibrillation and atrial flutter 

• ATTR is a disease of aging, so collaborating with geriatricians is important to help coordinate care and establish the patient’s individualized goals.  

8.  What is your management of subclinical ATTR and strategies for early detection? 

• Again, having a strong index of suspicion for cardiac amyloidosis is prudent.   

• The most common TTR variant that causes hATTR on earth is the V122I mutation (PV142I), which is very common in Western African ancestry. We suspect 1.5 million carriers of this variant in the USA alone, which puts individuals at 2-3x higher risk for heart failure than their age, sex, and race-matched non-carrier controls. 

• Expert consensus suggests monitoring individuals with this variant about 10 years before when the proband (i.e. if patient was diagnosed at 70, family members start screening at 60).  

• Initial work-up should include standard tests: ECG, echocardiogram, blood work. 

• Upcoming clinical trial will enroll patients in this critical 10-year window and randomize them into acoramadis vs placebo to see if treatment before symptom/disease onset can prevent amyloid disease. 

References

1. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC). Eur Heart J. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194 

2. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. DOI: 10.1056/NEJMoa2401424 

3. Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR amyloidosis: current and emerging management strategies: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2021;3(4):488-505. doi:10.1016/j.jaccao.2021.06.006 

4. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689 

5. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2024;390(2):132-142. doi:10.1056/NEJMoa2305434 

6. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793 

7. Benson MD, Waddington-Cruz M, Berk JL, et al. Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy. JAMA. 2023;330(1):37-46. doi:10.1001/jama.2023.10025. 

8. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153 

9. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):1-9. doi:10.1080/13506129.2022.2091985 

10. Redman M, King A, Watson C, King D. What is CRISPR/Cas9? Arch Dis Child Educ Pract Ed. 2016 Aug;101(4):213-5. doi: 10.1136/archdischild-2016-310459. Epub 2016 Apr 8. PMID: 27059283; PMCID: PMC4975809.  

11. Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021;385(6):493-502. doi:10.1056/NEJMoa2107454