ISSN Versión Online: 2308-0531 Rev. Fac. Med. Hum. April 2021;21(2):399-416. Facultad de Medicina Humana URP DOI 10.25176/RFMH.v21i2.3626 REVIEW ARTICLE

MANAGEMENT OF GENETIC DISEASES: PRESENT AND FUTURE

TRATAMIENTO DE LAS ENFERMEDADES GENÉTICAS: PRESENTE Y FUTURO

Hugo Hernán Abarca-Barriga1,2,3,a,b, Milana Trubnykova2,a, María del Carmen Castro-Mujica1,a

ABSTRACT Today, the number of genetic diseases is around 10000 conditions, affecting to 6%-8% of all populations. This review shows us how the discovery of genetic variants in our genome, this facilitated to know with precision about the mechanisms physiopathological, and hence to recognize those target points susceptible to modifications, through therapeutical strategies different thwi palliative proposals, increase life expectancy, or improve qualities of life. These therapies are diverse, using drugs for polygenic diseases, nutritional therapy, special formulas, enzyme replacement therapies, hematopoietic stem cell transplant, substrate reduction, oligonucleotides, and gene therapy. These genetic diseases are heterogeneous clinically with a very low frequency; nevertheless, open to the possibility of research in new strategies for more genetic disease, that today, furthermore, are orphans. REVIEW ARTICLE Key words: Genetic diseases; Genetic Therapy; Hematopoietic Stem Cells; Transplant; Therapy (source: MeSH NLM). RESUMEN El número de enfermedades genéticas se estima que podrían ser más de 10 000 condiciones diferentes, afectando alrededor del 6-8% de la población. La presente revisión nos muestra la importancia del descubrimiento de las variantes patogénicas en nuestro genoma que nos permite conocer con mayor precisión cuales son los mecanismos fisiopatológicos y, por lo tanto, conocer puntos dianas susceptibles de modificaciones mediante diferentes estrategias terapéuticas para poder palear los síntomas y signos, aumentar la expectativa de vida, mejorando así la calidad de vida de los pacientes que tienen algunas de estas enfermedades genéticas. Las diferentes terapias que existen en la actualidad son muy diversas como fármacos de uso en patologías comunes, terapia nutricional, fórmulas especiales, terapias de reemplazo enzimático, trasplante de órganos y células hematopoyéticas, reducción de sustrato, oligonucleótidos y la terapia génica. Al ser las enfermedades genéticas clínicamente heterogéneas, abre la posibilidad de poder investigar cada vez más nuevas estrategias en un mayor número de enfermedades que en la actualidad están olvidadas. Palabras clave: Enfermedades genética; Terapia genética; Células Madre hematopoyéticas; Trasplantes; Terapias (fuente: DeCS BIREME).

1 Facultad de Medicina Humana, Universidad Ricardo Palma, Lima-Perú. 2 Servicio de Genética & EIM, Instituto Nacional de Salud del Niño-Breña, Lima-Perú. 3 Universidad Científica del Sur, Lima-Perú. a MD Specialist in Medical Genetics. b Magister in Genetics. Cite as: Hugo Hernán Abarca-Barriga, Milana Trubnykova, María del Carmen Castro-Mujica. Management of genetic diseases: present and future. Rev. Fac. Med. Hum. April 2021; 21(2):399-416. DOI 10.25176/RFMH.v21i2.3626

Journal home page: http://revistas.urp.edu.pe/index.php/RFMH

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Pág. 399 REVIEW ARTICLE Pág. 400 prevalence between 1/1 000 to 1/25 000 syndromes; where themostfrequent have a CNVs that causemicrodeletion/microduplication entities to numbermore than10,000 Organization (WHO) diseases, whichare estimated by the World Health twoThe first variants mainlyproduce monogenic number ofcopies (CNV, copy numbervariation). multinucleotide variant) andiii)variants inthe variant), ii) variants of multiple nucleotides (MNV, variants inauniquenucleotide(SNV, nucleotide into three groups: i) the ones that are produced by origin. unknown The genetic origin can be divided 80% ofthetotal cases, andtheother20%hasan The etiologyofrare diseasehasageneticorigin in rare diseasemay bebetween 3.5%to 5.9%. estimate that the percentage of affected people by a people that theyare approximately 2millionofPeruvian number of affected people, therefore it isestimated there arecountry nostudiesthat definethe real between 6%to our 8%ofthegeneral population. In The numberofpatients whoare affected is estimated one withanincidence oflessthan1/2000people. That iswhy, for example, inEurope itisreferred asthe A rare diseaseisdefined by theappearance frequency. of CNVs ishigherreaching 0.7% that infetusesit hasbeenreported theincidence Down syndrome, Klinefelter syndrome) to that notallgeneticdiseasesare clarify rare. (e.g. for upto 71%ofpediatric hospitalizations shouldbenoted that geneticdiseasesaccountIt targeted treatment large group ofconditions, about500diseaseshave a generated 10.5%ofhospitalexpenses in2010found that patientscohort withrare diseases Australian outinapopulation-based studycarried large onhealthsystems; economic thus, impact an group cause between 20%and30%ofdeaths inthisage genetic conditions to alongerhospitalstay thantheirpeerswithout Rev. Fac. Med. Hum. 2021;21(2):399-416. INTRODUCTION (8) (1) (1) . ofpatientsThis generates proportion a . Nonetheless, some studiesthat were done . Pathogenic (orprobably pathogenic) (7) (6) . . (4) . It is important isimportant . It (9) , inaddition (3) (5) ; although, . Of this . Of (7) and by bioinformatics progressively andsteadily increasing, whichisaided that initiate orfactors factor thedisease, have been therapies, namely thosethat are directed at the the pathophysiology ofgeneticdiseases, targeted decoding ofDNAandabetter understandingof Since theendof20thcentury, thanksto the such astheFood andDrugAdministration (FDA use has been approved by international institutions Therapies for geneticdiseasesare available andtheir prenatal to adulthood genetic diseasescanappearat any stageoflife, from genetic cause is now considered that upto 20%ofcaseshave a component was notpreviously andit described such asinfantile cerebral palsy, inwhichagenetic movements andcancer. There are even entities, disorder,deficit hyperactivity dementia, abnormal disorders,spectrum disorders, conduct attention immunodeficiencies, schizophrenia, autism primary stature,congenital anomalies, short microcephaly, disability,intellectual epilepsy, neuroregression, hypotonia, delayed psychomotor development, andcanmanifest variability as or phenotypic diverse,are very i.e. theyhave agreat clinical The clinicalmanifestations ofgeneticdiseases and theEuropean (EMA) Agency Medicine substrate therapy) reduction andsymptomatic the metaboliccascade(e.g. specialformulations, hematopoietic cell transplantation), modifying therapy), replacing protein theabnormal (e.g. the affected gene(s) (e.g. geneandchromosome diseases. Thus, treatment could beat thelevel of points ofthepathophysiological cascadeofgenetic approach outisfocused iscarried ononeofthe genetic diseases. The way inwhichatherapeutic existing andwhat isbeinginvestigated inthese way thepharmacological treatment currently this review toIn identifywe in a general aim to try trials portal withmore than2,520different portal trials studies them inclinicalresearch, ascanbeseenintheclinical treatments whichare inbasicresearch andsomeof the otherhand, there isagreat ofnew expectation (Figure 1). (1) . It is important to point outthat isimportant . It (11) . (10) . Abarca Het al (14,15) . On (12,13) (16) (17) .

REVIEW ARTICLE (19) Pág. 401 Pág. HSCT Management of genetic diseases: present and future and present diseases: genetic of Management special formulas 67% Symptomatic management Symptomatic Gene therapy Therapeutics in research Therapeutics therapy, chaperones, chaperones, therapy, Enzyme replacement Enzyme replacement proteostasis modulators, modulators, proteostasis Substrate replacement therapy, therapy, replacement Substrate (19) When research began, it focused mainly on it focused began, research When most currently However, monogenic diseases. cancer at directed studies are clinical research 2). (Figure (17) 2% 1% 2% faulty 12% Protein complex substratum Genetic defect Accumulation of Accumulation Worldwide Gene Therapy Clinical Trials Symptoms of disease Symptoms Pathogenic waterfalls Pathogenic 6% 6% Cell dysfunction death and Cell 0% Source: 2% 2% Sphingolipid lysosomal storage disorders storage Sphingolipid lysosomal :399-416. . (18) Fuente: Therapeutic approach to genetic diseases. Some genetic conditions may involve one or more of of more or one involve may Some conditions genetic diseases. genetic to approach Therapeutic Proportion of diseases using gene therapy in clinical trials. Genetic diseases are the second most the second Genetic diseases are in clinical trials. of diseases using gene therapy Proportion

GENE THERAPY GENE frequently investigated group of conditions. Source: Gene Therapy Clinical Trials Worldwide (19). Worldwide Trials Clinical Therapy Gene Source: of conditions. group investigated frequently Figure 2. Figure Figure 1. Figure any of these links. For example, phenylketonuria can be managed by decreasing the amount of substrate of substrate the amount decreasing can be managed by phenylketonuria example, For of these links. any Sphingolipid lysosomal Source: or enzyme therapy. special formulas through replacement (phenylalanine) (17). disorders storage The main objective of gene therapy (also known main objective as of gene therapy The a long- incorporate sufficiently to is therapy) gene transgene or gene therapeutic a of expression lasting minimal with symptoms cure or improve to order in events adverse Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 402 vivo There are ofgenetransfer: two types in-vivo andex- and thenincorporated backinto theaffected from thepatient,extracted thegeneisdelivered todirectly atissue, whileinthelatter, cells are double-stranded DNAisthenincorporated intodouble-stranded thehostgenome. host cell, this RNAusesacomplex DNA. to reverse produce double-stranded transcription machinery This retroviruses (RNA) viruses, derived theincorporation from after ofRNA into humanimmunodeficiency the host cell, thegeneticmaterial isnotincorporated into thehostgenome. C.Lentivirus. They are of asubtype (Episome). B. Adenoassociated viruses. ofthe infection Constituted DNA,andafter by a single-stranded thehostcell,"infecting" thegenetic material isnotincorporated into thegeneticmaterial ofthehost Figure 3. diseases) itshouldbeshort diseases(e.g.while inmultifactorial cancer, infectious monogenic diseasesthetimeshouldbeprolonged, ofpathology,depends onthetype for example, in duration oftheexpression ofthetransferred gene cells oreggcells) (sperm orsomatic cells. The of gene Thetherapies are types directed to germ Rev. Fac. Med. Hum. 2021;21(2):399-416. (21) . The former meansthat thegeneisdelivered

A. Adenoviruses. They are constituted by adoublestranded (doublestranded) DNA,after A B C (20) . well asgeneediting nucleotides, as synthetic short and nanoparticles, subdivided into thoseusingvirus-mediated therapy individual adeno-associated viruses,adeno-associated lentivirus, retrovirus The mostfrequently used virusesare: adenovirus, inflammatory response inflammatory to infect differentcapacity tissuesandhave alower commonly usedbecausetheyhave agreater (Figure 3). Adeno-associated viruses are the most VIRUS-BASED THERAPIES (18,21) . ofgenetherapyThe types canbe (22) . (20) . Abarca Het al (23,24)

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(22,31-33) Pág. 403 Pág. . (30) (Figure 4B). (Figure (22,31-33) Management of genetic diseases: present and future and present diseases: genetic of Management Antisense oligonucleotides (AON, from antisense from oligonucleotides (AON, Antisense of DNA, 20-30 nucleotides oligonucleotide), have of action: in which forms with two i) using RNA Hase, withoutii) and (mRNA) RNA messenger destroys it actcan it modulating where by Hase, RNA using the 5' blocking, binding to steric through splicing, of mRNA or the 3' poly A region cap region (AAV9), which is used for spinal muscular atrophy atrophy muscular spinal for is used which (AAV9), presenting children who are #253300), (MIM 1 the where hypotonia, congenital progressive a majority (95-98%) present of those affected the SMN1 gene 7 of exon deletion in ARN de interferencia (ARNi), se utilizan comoutilizan se (ARNi), interferencia de ARN los virus ARN. contra natural mecanismo de defensa la utilización es mediante El mecanismo de acción (ribonucleasa) Dicer moleculares de los complejos silencing complex), RNA-induced inglés, (del RISC y al ARNm complementaria yuniéndose de manera rompimiento su posterior (Figure 4A). (Figure THERAPIES WITH SHORT SHORT WITH THERAPIES NUCLEOTIDES Among the therapies that use short that therapies the Among synthetic types: two are there nucleotides, a. b. . (26) . (27) . (28) :399-416. . A (29) : (18,25) Alipogene tiparvovec -Glybera- tiparvovec Alipogene is an for used adeno-associated(AAV1) virus type #238600)(MIM 1 hyperlipoproteinemia gene, LPL the of variants recessive by caused causing lipase deficiency, lipoprotein leading to and pancreatitis hyperchylomicronemia Strimvelis, uses a retrovirus as a vector, which as a vector, uses a retrovirus Strimvelis, deaminase deficiencyis used in adenosine combined severe by gene), characterized (ADA immunodeficiency (MIM #102700) Zynteglo, using a lentivirus as a vector, is used in as a vector, using a lentivirus Zynteglo, characterizedbeta-thalassemia (MIM #613985), microcytic anemia, hypochromic congenital by Hb hemoglobin (Hb)F, A and increased decreased hepatosplenomegaly Voretigene neparvovec-rzyl -Luxturna- (AAV2), neparvovec-rzyl -Luxturna- (AAV2), Voretigene of the variants the use of recessive for approved amaurosis congenital causes Leber RPE65 gene that 20 (MIM pigmentosa (MIM #204100) and retinitis #613794) Onasemnogene abeparvovec-xioi -Zolgensma- Onasemnogene abeparvovec-xioi -Zolgensma- a. Since 2016 to date, virus-based genotherapies have have genotherapies virus-based date, to 2016 Since mention which we and EMA), FDA (by been approved below b. c. d. e. Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 404 Rev. Fac. Med. Hum. 2021;21(2):399-416. a. a. by theFDA and/orEMA: To date, we have thefollowing moleculesapproved b. b. c. c. Figure 4. Employed by RNAinterference (RNAi). functionality protein,resulting however, in a short with greater ofthisexon the DMDgene;causingaskipping and whopresent thedeletionofexon 51of musculardystrophyDuchenne (MIM#310200) Eteplirsen: isanAON usedinpatients with protein similarto SMN1 SMN2 gene (which is usually decreased), being a the SMN2gene, modifyingtheexpression ofthe is usedinpatients whohave at leastonecopy of variants of the SMN1gene.homozygous This AON atrophy 1(MIM#253300),which iscausedby type Nusinersen: isanAON usedinspinalmuscular protein This ofthe"mutant" RNAi causesthe reduction heterozygous monoallelicvariants inthe gene. TTR amyloidosis (MIM#105210),causedby hereditary Paitisiran: isanRNAi usedintransthyretin-related (39)

. Mechanisms of action of short nucleotidesA.Used by OAS ofshort to alter ofaction messengerRNA(mRNA).Mechanisms B. B (34,35) . (36-38) . d. d. betatalasemia, urea disorders cycle fibrosis, 1,cystic tyrosinemia type hereditary congenital muscular dystrophy, Duchenne cataract, diseasesunderbasicresearchMonogenic include 5E), epigeneticmodification to genomeimaging. 5A). Uses range from generegulation (Figure 5B- 9) andasimpleguidesequence (sgRNA) (Figure Cas 9contains two elements, an endonuclease(Cas archae, whichconfers resistance to viruses. CRISPR/ system is based on a system found and in bacteria repeat /CRISPRassociated protein 9). The latter (clustered palindromicregularly interspaced short (transcription activator-like repeat) andCRISPR/Cas9 nucleases such as ZNF (zinger nuclear finger), TALE the useofgeneeditingthrough meganucleases, that greaterknow possibilitiesare openingupwith to On theother hand, itis of utmost importance GENETIC/GENE EDITION PCSK9 genes) hypercholesterolemia (variants intheLDLR,APOB, isanAON Mipomersen: usedinfamilial (40) . (41) . Abarca Het al REVIEW ARTICLE . Pág. 405 Pág. (45,46) . We can divide this We . (44) (Table 1): (Table Management of genetic diseases: present and future and present diseases: genetic of Management (45,46) . . (45,46) (47,48) Nutrient restrictionNutrient in a toxic is an increase it is knownWhen there that in enzymatic a decrease due to activity, metabolite cascading other metabolites are there and that these through reduce is done is to what above; decrease, to toxic the causing formulas, special the onset of the pathophysiological thus avoiding cascade Nutritional supplementation apart cases, In nutrient restriction with from many necessaryis it supplement to formulas, special not adequately are that with metabolites produced metabolite or blocking Elimination of toxic synthesis the pathophysiology IEM, where many are There in the alternative of the picture is mainly framed metabolism, so it is production of a toxic the (e.g. necessary use drugs or procedures to defects) that in urea cycle use of hemofiltration of these or block the synthesis eliminate a. type of therapy into type of therapy b. c. possible through universal neonatal screening of at of at screening neonatal universal possible through entities least the most frequent . It. (43) . (20) . These NPs have the have NPs These . (23) A . On the other hand, the . On the other hand, . It is important emphasize to (23) :399-416. (42) CRISPR/Cas9 A. CRISPR/Cas9 system. PAM= protospacer adjacent motif, N=A, R=G or A. = Cas9 Cas9 = A. or R=G N=A, motif, adjacent protospacer PAM= system. CRISPR/Cas9 A. CRISPR/Cas9

. These nanoparticles These of composed be can . (23) B Figure 5. Figure protein. Sg=single guide. Mechanisms of action of the CRISPR/Cas9 system. B. Cas9 and sgRNA cause gene Cas9 B. Mechanisms of action system. Sg=single guide. the CRISPR/Cas9 of protein. and two insertdisruption (knock plus one DNA strand Cas9 sgRNAs two out). C. Cas9, a gene (knock in). D. ("mutation"). correct a genetic variant sgRNA and a DNA template Cas9, E. a gene. deletes sgRNAs GENE THERAPY USING NON-VIRAL USING THERAPY GENE VECTORS NUTRITIONAL THERAPY NUTRITIONAL These are research strategies that have the possibility have that strategies research are These vectors, synthetic DNA through of incorporating known as nanoparticles frequently which are (NPs) nm 500 measuringto 10 polysaccharides, solid lipids or coated with CK30PEG solid lipids or coated polysaccharides, with 10KDa conjugated polylysine (30-mer cationic glycol) polyethilene advantage of very easy synthesis, lower production of very lower advantage synthesis, easy the safety, greater vectors, than viral costs capacity transport to molecules and greater larger efficacy that there are at least 81 pathologies that, with earlywith that, pathologies 81 least at are there that the risk will prevent and timely treatment, diagnosis intellectualof disability (www.treatable-id.org) This type of therapy is mainly used for inborn errors inborn errors is mainly used for typeThis of therapy of metabolism (IEM) is of utmost importance to emphasize that the ideal the importanceutmost of is that emphasize to if and earlyas is possible, as diagnosis of moment incorporation of DNA is being tested with the use with the of DNA is being tested incorporation means of physical by ("naked" DNA) of a vector sonoporation, electroporation, as such methods and "bullet" genes magnetofection Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 406 Rev. Fac. Med. Hum. 2021;21(2):399-416. Table 1. Management of some inborn errors of amino acid, carbohydrate and lipid metabolism.

Supplementation, Clinical features without timely dietary, Disease Enzyme deficiency Mim o ps Special formulation References treatment considerations and other treatments

Aminoácidos

L-tyrosine, long Phenylalanine, profound and irreversible Phenylalanine ฀phenylalanine and Phenylketonuria 261600 neutral amino acids, 47, 48 intellectual disability. hydroxylase ฀tyrosine tetrahydropterin

Phenylalanine.Do not respond adequately Hyperphenylalaninemia, to special formulations with FA , RDPM, Dihydropteridine quinoid ฀phenylalanine and 261630 Tetrahydropterin: 2mg/kg 48 BH4 deficiency DI, axial hypotonia and appendicular reductase ฀tyrosine hypertonia, epilepsy.

Succinylacetone, tyrosine, FA, ฀phenylalanine and Tyrosinemia Ia, Ib methionine. Severe liver disease, renal Fumarylacetoacetate 276700 NTBC 1-2 mg/kg/day 49 ฀tyrosine tubular disorder, rickets.

Tyrosine , normal FA. Herpetiform corneal ฀phenylalanine and 3-omega fatty acid Tyrosinemia II ulcers and punctate keratosis of fingers, Tyrosine transaminase 276600 50 ฀tyrosine supplementation palms and soles, DI.

Dihydrolipoamide branched-chain ↑Leucine, ↑isoleucine, ↑valine. Maple syrup-colored urine transacylase, BCKA beta- Oral thiamine: 100-300 mg/ Matchstick maple syrup od or, neonatal 248600 ฀Leucine 50 disease subunit decarboxylase, day. L-Valine, L-isoleucine encephalopathy. BCKA alpha-subunit decarboxylase.

Isovalerylacidemia, metabolic acidosis, Abarca Het al Isovaleryl CoA L-carnitine: 100 mg/kg/day. Isovaleric acidemia RDPM, epilepsy, cerebral hemorrhage, 243500 ฀Leucine 51 dehydrogenase Glycine 200-400 mg/kg neutropenia, leukopenia, pancytopenia.

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cardiomyopathy. cardiomyopathy.

CoA carboxylase carboxylase CoA 100 mg/kg/day. mg/kg/day. 100

threonine, valine valine threonine,

methylmalonic acidemia acidemia methylmalonic disorder, chronic renal disease, disease, renal chronic disorder,

251000 407 Pág.

mutase and propionyl propionyl and mutase 10-20 mg/day. L-Carnitine: L-Carnitine: mg/day. 10-20 57

mtinn,isoleucine, ฀methionine, Propionic and and Propionic ammonium. Early death or neurologic neurologic or death Early ammonium. 606054 y y 606054

Methylmalonyl CoA- Methylmalonyl Biotin: 5-10 mg/day. B12 B12 mg/day. 5-10 Biotin:

Acute deterioration, metabolic acidosis, acidosis, metabolic deterioration, Acute

hepatomegaly and muscular hypotonia. hypotonia. muscular and hepatomegaly

intolerance intolerance familiy 7, member 7) 7) member 7, familiy 4 doses. doses. 4

poenitk intake ฀protein episodes, aversion to protein-rich foods, foods, protein-rich to aversion episodes, 222700 56

Lysinuric protein protein Lysinuric SLC7A7 (solute carrier carrier (solute SLC7A7 L-citrulline: 2.5-8.5 g/day in in g/day 2.5-8.5 L-citrulline: Lysine. Recurrent vomiting, diarrhea, coma coma diarrhea, vomiting, Recurrent Lysine.

Management of genetic diseases: present and future and present diseases: genetic of Management

ganglia lesions. lesions. ganglia

dehydrogenase dehydrogenase day. day.

lsn n ฀rpohn ฀tryptophan and ฀lysine Glutaric acidemia type 1 1 type acidemia Glutaric encephalopathy, macrocephaly, basal basal macrocephaly, encephalopathy, 231670 55

Glutaryl CoA CoA Glutaryl Riboflavin: 100-300 mg/ 100-300 Riboflavin:

Glutaric acid, glutaconic acid. Acute Acute acid. glutaconic acid, Glutaric

20 mg (oral). (oral). mg 20

mg/day. B12 1 mg (IM), 10- (IM), mg 1 B12 mg/day.

csen ฀cysteine

mg/day. Pyridoxine 25-750 25-750 Pyridoxine mg/day. 54 Homocystinuria Homocysteine, ectopia lentis, RDPM, DI DI RDPM, lentis, ectopia Homocysteine, Homocystinuria 236200 β-synthase Cystathionine

฀methionine and and ฀methionine

times per day. Betaine: 150 150 Betaine: day. per times

Folic acid: 500-1000/ mg/ 3 3 mg/ 500-1000/ acid: Folic

3-methylglutaconic aciduria are observed. observed. are aciduria 3-methylglutaconic 15-150 mg/day. mg/day. 15-150

aciduria aciduria quadriplegia, dystonia, hyperreflexia, hyperreflexia, dystonia, quadriplegia, kg/day. Pantontenic acid: acid: Pantontenic kg/day.

Luie ฀Leucine 9 different enzymes PS250950 enzymes different 9 53

3-Methylglutaconic 3-Methylglutaconic 1, lack of medro, optic atrophy, spastic spastic atrophy, optic medro, of lack 1, day. Glycine 250-400 mg/ 250-400 Glycine day.

3-methylglutaconic aciduria. In type type In aciduria. 3-methylglutaconic L-carnitine: 100 mg/kg/ 100 L-carnitine:

:399-416.

dehydrogenase. dehydrogenase.

semialdehyde semialdehyde

aciduria. aciduria.

vln ฀valine 3-OH-isobutyric aciduria aciduria 3-OH-isobutyric methylmalonate methylmalonate 236795 -antn:10m/gdy 52 mg/kg/day. 100 L-carnitine:

Organic acidemia, lactate, 3-OH-isobutyric 3-OH-isobutyric lactate, acidemia, Organic

chain or defects of of defects or chain Defects of the respiratory respiratory the of Defects Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 408 Rev. Fac. Med. Hum. 2021;21(2):399-416. Carbamoyl phosphate Ammonium , in cases with severe ↑↑↑ synthetase I, ornithine enzyme deficiency, lethargy, anorexia, L-arginine: 200-400 mg/ transcarbamylase, hyper- or hypoventilation, consvulsions kg. L-citrulline: 200-400 argininosuccinic and coma are observed. In cases with mild mg/kg/day. Sodium acid synthetase, Urea cycle disorders deficiency, ammonium is elevated due to Heterogeneous ฀amino benzoate: 250-500 mg/kg/ 58 argininosuccinic acid a trigger (acute illness or stress), with loss day, hemofiltration and lyase, arginase, N-acetyl of appetite, vomiting, lethargy, delusions, hemodialysis with ECMO, glutamate synthetase, hallucinations, psychosis and acute carbamyl glutamate. ornithine translocase, encephalopathy. citrinase.

Carbohydrates

Galactose 1-phosphate↑. Swallowing problems, failure to thrive, hepatocellular Galactose 1-phosphate Eliminate galactose (lactose, Classic galactosemia damage, bleeding, E. coli sepsis, RDPM, 230400 Soy milk. Elemental calcium 59 uridylyltransferase galactolipids) language disorder, premature ovarian failure, cataract.

Hepatomegaly, nephromegaly, hypoglycemia, lactic acidosis, uric acid↑, Glucose 6-phosphatase Compound carbohydrates: Eliminate lactose, fructose, Glycogenosis type I lipids↑, triglycerides↑, seizures. "Doll" or glucose 6-phosphate 232200 raw starch (1.5-2 g/kg/ 60 sorbitol facies, short stature, chronic neutropenia, transporter dose). Dietary fractionation xanthoma, diarrhea.

Glucose, lactic acidemia, phosphorus ↓, uric acid ↑,, magnesium ↑, alanine↑. Nausea, Hereditary fructose Fructose 1-phosphate vomiting, lack of medro, acute lethargy, 229600 ฀Fructose <10 mg/kg Vitamin C 61 intolerance aldolase convulsions, coma. Hepatic and renal failure.

Lipids

Cationic organic transporter 2, carnitine palmitoyltransferase L-carnitine: 100 mg/kg. Long-chain fatty acid Hypoglycemia, ketones↓↓↓, insulin ↑ free ฀Lipid s: 15-20 % of total type 1A and 2, carnitine- Heterogeneous Dietary fractionation. MCT: 62 oxidation defects fatty acids↓. Cardiomyopathy, myopathy. calories acylcarnitine translocase, 30% of total lipids, DHA VLCAD, mitochondrial Abarca Het al trifunctional protein FA= phenylalanine, RDPM= psychomotor developmental delay, DI= intellectual disability, NTBC=, ECMO=extracorporeal membrane oxygenation. VLCAD= very long chain acyl-CoA dehydrogenase. REVIEW ARTICLE Pág. 409 Pág. (Table 2). (Table . (Figure 6). . (Figure (68) (69-78) Management of genetic diseases: present and future and present diseases: genetic of Management . (65,66) by delivering the defective protein will change the protein the defective delivering by of this group Within history natural of the disease. depot diseases and adenosine lysosomal are entities deaminase deficiency It is of utmost importance of the effectiveness that as lesser degree or a greater will depend to therapy minimally or is asymptomatic long as the patient affected supposed to affect all to supposed types of tissue-bound myeloid possibly and cells including myeloid populations, HSCT reason, this was For brain. the in microglia enzyme-deficient treating for an avenue as intended nervous (CNS) central system with severe patients donor if complete Importantly, involvement. HSCTchimerism is achieved, intervention is a unique of enzymes source for lifelong a capable of providing re-establishcells also The donor patient. the affected overcoming patient, in the system immune a new pre-existingpost-treatment preventing and ones the functional at directed immune responses patients the first LSD enzyme. since On this basis, thousand a few in the early 1980s, transplanted were HSCT with allogeneic treated been have LSD patients past decades the over . (64-67) :399-416. Mechanism of action of hematopoietic cell transplantation. The donor cell will synthesize the will synthesize cell donor The Mechanismtransplantation. of actioncell hematopoietic of

ENZYME REPLACEMENT THERAPY REPLACEMENT ENZYME (ERT) deficient enzyme (E), which will be captured by the deficient cells, through the 6-phosphate mannose the 6-phosphate through cells, enzymedeficient by the deficient (E), which will be captured the metabolic complexes. degrade subsequently to the lysosome into this complex (M6), integrating receptor There are many pathologies of genetic origin that that of genetic origin pathologies many are There Figure 6. Figure HEMATOPOIETIC CELL HEMATOPOIETIC TRANSPLANTATION The rationale for applying HSCT for storage rationale in lysosomal The ability is based on the diseases (LSD) of transplanted (or clones) to progeny cell and/or their cells of populations the macrophage to contribute local permanent tissues and thus become affected of functional enzymes; lysosomal sources this in the can improve metabolically active cells way material storage disease phenotype removing by at diseased sites. local inflammation and modulating is with the donor after transplantation turnover Cell Known as hematopoietic stem cell transplantation transplantation cell stem Known as hematopoietic (HSCT), genetic in different widely used which is and proven is available typeThis of therapy diseases. for primary effective immunodeficiencies congenital imperfecta Duncan osteogenesis disease), (e.g. (Figure (LSD) diseases storage and lysosomal adrenoleukodystrophy, X-linked 6), such as VII; metachromatic VI and I, II, mucopolysaccharidosis and mannosidosis fucosidosis leukodystrophy, Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 410 Rev. Fac. Med. Hum. 2021;21(2):399-416. Table 2. Enzyme replacement therapy in genetic diseases.

Approved TRE ntity MIM Affected gene Main clinical characteristics References (FDA and/or EMA)

Coarse facies, macrocephaly, skeletal dysplasia, 607014, 607015, hepatosplenomegaly, variable neurological involvement, Mucopolysaccharidosis I IDUA Laronidase 74,75 607016 pulmonary and cardiac involvement, progressive joint contractures, corneal opacity.

Coarse facies, macrocephaly, skeletal dysplasia, hepatosplenomegaly, variable neurological involvement, Idursulfase 74,75 Mucopolysaccharidosis II 309900 IDS pulmonary and cardiac involvement, progressive joint Hunterase 78 contractures, claw hand.

Coarse facies, skeletal dysplasia predominantly thoracic, Mucopolysaccharidosis 253000 GALNS pulmonary and cardiac involvement, corneal opacity, Elosulfase alfa 74,75 IV A hyperlaxity in hands.

Coarse facies, macrocephaly, skeletal dysplasia, Mucopolysaccharidosis VI 253200 ARSA hepatosplenomegaly, pulmonary and cardiac involvement, Galsulfase 74,75 progressive joint contractures, claw hand.

Progressive loss of muscle strength, at birth can be observed Pompe Disease 232300 GAA Alglucosidase alfa 70 as hypotonia and cardiomegaly. Abarca Het al Imiglucerase Gaucher Disease 230800 GBA Thrombocytopenia, splenomegaly, bone involvement. Velaglucerase 81 Taliglucerase

REVIEW ARTICLE

years of age). age). of years

lipofuscinosis type 2 2 type lipofuscinosis 411 Pág.

myoclonic ataxia, pyramidal signs, visual impairment (4-6 (4-6 impairment visual signs, pyramidal ataxia, myoclonic TPP1 204500 Cerliponase alpha alpha Cerliponase

Neuronal ceroid ceroid Neuronal

Onset at 2-4 years of age with epilepsy, neuroregression, neuroregression, epilepsy, with age of years 2-4 at Onset

hnleoui 261600 Phenylketonuria sdi dl ainswt hnleoui. Pgaae 77 Pegvalase phenylketonuria. with patients adult in Used PAH

Management of genetic diseases: present and future and present diseases: genetic of Management

lymphocytes. lymphocytes.

deficiency deficiency

of toxic metabolites causing malfunction and formation of of formation and malfunction causing metabolites toxic of ADA 102700 E-D 70 PEG-ADA

Adenosine deaminase deaminase Adenosine

Severe combined immunodeficiency due to accumulation accumulation to due immunodeficiency combined Severe

Cirrhosis, hypersplenism, intestinal malabsorption. malabsorption. intestinal hypersplenism, Cirrhosis,

deficiency deficiency

of the adrenal glands. Cholesterol ester deposition disease. disease. deposition ester Cholesterol glands. adrenal the of LIPA 278000 eeiaeaf 76 alfa Sebelipase

Lysosomal acid lipase lipase acid Lysosomal

Malnutrition, hepatomegaly with hepatic failure, calcification calcification failure, hepatic with hepatomegaly Malnutrition,

"myopathy", early loss of deciduous teeth, short stature. stature. short teeth, deciduous of loss early "myopathy",

yohshtsa 210,211 ALPL 241510 241500, Hypophosphatasia presentation from pathological fractures, chondrocalcinosis, chondrocalcinosis, fractures, pathological from presentation soaeapa 73 alpha Asfotase Decreased bone and dental mineralization. Variable Variable mineralization. dental and bone Decreased

:399-416.

cardiac involvement, cornea verticilata, verticilata, cornea involvement, cardiac Agalsidase beta beta Agalsidase

ar ies 301500 Disease Fabry AGA 69,79

Acroparesthesias, angiokeratomas, chronic renal disease, disease, renal chronic angiokeratomas, Acroparesthesias, Agalsidasealpha Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 412 mucopolysaccharidoses (e.g. III) type in that genistein hasthismechanismofaction C(MIM#257220) type 1(MIM#230800)andNiemann-Pick as Gaucher held as therapeutic weapons for diseases such affected pathway.Miglustat andeliglustat are the metabolite(s) onestep upstream ofthe Substrate therapy reduction consists ofreducing protein ofa ofstabilizingthe usual activity function disease (MIM#301500).Chaperones have the iscurrentlyMigalastat approved for use in Fabry Rev. Fac. Med. Hum. 2021;21(2):399-416. a. a. copias enlascélulas (Figure trisómicas 7A). una forma inducibledelgenXISTenunadelas consiste en utilizarnucleasas(ej. ZNF) para insertar Silenciamiento decromosomas con XIST, elcual se tiene parciales ototales. Dentro delasestrategias utilizadas mejorar elefecto delasduplicacionesodeleciones encuentraSe eninvestigación básicaysebasaen SUSTRATO TERAPIA DE REDUCCIÓN DEL CHAPERONAS CHROMOSOME THERAPY to imperfect efficiency, onlysometo cellsinthe imperfect resistance to ganciclovir. and sensitivity Due a TKNEO transgene that confers neomycin (NEO) viralan adeno-associated vector (AAV) containing inducible pluripotent stem cells) are infected with population.a trisomic The cells fullytrisomic (iPSCs- with antibiotics and then isolate disomic cells from transgene isused, whichhelpsto select (TKNEO) chromosome; thethymidine kinase-neomycin Positive-negative ontheextra markers selectable (79) (84,85) . : (80–82) . There are many reviews (83) . e. e. d. c. b. inhibitory controlinhibitory andadaptive behavior improving cognition, visual recognition memory, epigallocatechin-3-gallate (green tea extract), patients (phase2)withDown syndrome is andsafetydemonstrated inadult itsefficacy of Down syndrome. Oneofthedrugsthat has physiopathology disability of the intellectual demonstrated that thisgeneisinvolved inthe oftheDYRK1AInhibition gene, ithasbeen chromosome naturally, restoring thedisomicstate. then thesecells replicate andlosethering that induces theformation chromosomes, ofring Cas9. Then thecells are treated witharecombinase ofthechromosomeand longarm through CRISPR- cellstrisomic (iPSCs)LoxP into theshort isinserted chromosome ofring formation. In Induction deletions. time, whichwould have ofcorrecting thepossibility These are freely integrated into over thecell cycle minichromosomes, whichare usedas"vectors". known chromosomes); as human artificial humanchromosomes (HAC-Artificial cells by 24%. which increases thenumberofeuploid(normal) (trisomy 21and18)are cultured withZSCAN4, Drug-induced rescue; trisomic where cells trisomic (Figure 7B). population that canbeisolated andproliferated cells are removed leaving onlythepure disomic and all trisomic TKNEO transgene-containing cellstrisomic isthentreated withganciclovir (GCV); events to occur naturally. ofdisomicand The cohort transgene isproliferated to allow nondisjunction are removed. The population containing the pure the cells that donotcontain the TKNEO transgene population istreated withneomycin, which after population receive the TKNEO transgene. The cell (86,87) Abarca Het al . REVIEW ARTICLE Pág. 413 Pág. . (92) . . (93) (90,91) Management of genetic diseases: present and future and present diseases: genetic of Management . (67) Tuberous sclerosis (MIM #PS191100) has very sclerosis Tuberous and the clinical manifestations heterogeneous such inhibitors the use of mTOR has approved FDA rhabdomyosarcomas, epilepsy, for everolimus as for rapamycin and angiomyolipomas; astrocytomas, lymphangioleiomyomatosis X-linked hypophosphatemic rickets (MIM #307800) hypophosphatemic X-linked hypophosphatemia in which chronic is a condition is observed in mineralization which causes a failure monoclonal A ricketsosteomalacia. and to leading be to shown been has (burosumab) inhibitor FGF23 in this condition therapy a promising Other imperfectain osteogenesis therapies the risk been observed of decrease to have that the activation of osteoclasts is through fractures (teriparatide, anabolic agents bone (denosumab), romosozumab) In this same sense, the use of bisphosphonates of bisphosphonates the use In this same sense, imperfectaas osteogenesis in diseases such (PS166200) and McCune-Albright (MIM syndrome pain and the risk of reduce to indicated #174800) are of fractures the appearance . (88) :399-416. A. Silencing of aneuploid chromosomes by inserting XIST. In (iPSCS) the XIST trisomic cells inserting by A. Silencing of aneuploid chromosomes XIST. .

(89) B A Figure 7. Figure (red) is incorporated into one of the chromosomes by ZNF, then the cells are treated in order to activate activate to in order treated are the cells then ZNF, by one of the chromosomes into is incorporated (red) observed which is subsequently (red), as a extra chromosome thus silencing the entire the XIST, (transcribe) selectableof Use positive-negative markers re-establishing extrathe on B. Barrcorpuscle, state. "disomic" a chromosome. OTHER THERAPIES OTHER Some monogenic diseases currently have therapies therapies have Some diseases currently monogenic be verified which could under clinical investigation, www.clinicaltrials.com. at not probably are Some shown therapies of the 1; is described on what in Figure directly focused enormous have to been shown they have however, utility of these diseases. in the management is a pathology (DMD) Duchenne muscular dystrophy loss of muscle strength progressive by manifested currently are therapies Three in the first decade. in short mentioned them we one of available, the use and the others are nucleotide therapies, of deflazacort Deflazacortataluren. and has been however, than 30 years; more widely used in DMD for in 2017 the FDA by only approved it was Ataluren is used in those patients who have a have who is used in those patients Ataluren Its (10-15% of DMD patients). nonsense variant mechanism of action perform is to jump at a reading making variant, of the nonsense the site the protein it In this way protein. than the "mutated" larger Beckercauses the phenotypemuscular change to to dystrophy Rev. Fac. Med. Hum. 2021;21(2) Hum. Med. Fac. Rev. REVIEW ARTICLE Pág. 414 Rev. Fac. Med. Hum. 2021;21(2):399-416. insurance coverage, amongothers. specialists, lackofimplementation, highcosts, is diagnosis, eitherdueto thelimited numberof entities. However, thebottleneckintheseconditions are ofthisgroup changing thenatural of history As we are seeinginrecent years, thesenewtherapies etiologically unrelated. will beusedinmore thanoneentity, whichare even specific; however, drugsare beingdeveloped that notably over to time. bevery Many therapies try The pharmacopoeia ingeneticdiseasesisincreasing E-mail: Telephone number: Address: Correspondence: Interest conflict: Financing: preparation ofthisresearch ofthemanuscript work. andinterpretation,collection analysis ofresults and design, in thegenesisofidea,project data Authorship contributions: 8. 7. 6. 5. 4. 3. 2. 1. BIBLIOGRAPHIC REFERENCES CONCLUSION Genomic Genomic Tests. 2012,4:e4f9877ab8ffa9. DOI:10.1371/4f9877ab8ffa9 Diagnostic Testing for Recessive ChildhoodDiseases. PLOS Curr Evid S.ComprehensiveKingsmore Screening Carrier andMolecular 74(1):121–7. DOI:10.1086/381053 Careon Inpatient in a Children’s Hospital. Am 2004; J Hum Genet. McCandless SE, BrungerJW, Cassidy SB. The Burden Disease ofGenetic DOI: https://doi.org/10.3389/fonc.2019.00297 et al. Gene Therapy Leaves a Vicious Cycle. Front Oncol. 2019;9:297. D, R,SubramanianGoswami G,Silayeva I,Doctor L,Newkirk Chawla K, 2012. 1oEdición. pediátrica. Atlas Fondo dedismorfología Editorial delINSN; Eva, Chávez,Klein, Gallardo, Abarca-Barriga, Miguel, Hugo. Bertha, 2015;35(8):801–9. DOI:10.1002/pd.4613 microduplications inover 9500pregnancies. Prenat Diagn. L, etal. Prevalence ofrecurrent pathogenic microdeletions and D,Grati Gomes FR,Molina Ferreira JCPB, Dupont C,Alesi V, Gouas DOI: 10.3928/19382359-20180419-01 and Microduplication Syndromes. Pediatr Ann. 2018;47(5):e198–203. Goldenberg P. An Update onCommon Chromosome Microdeletion 2019. 28(2):165-173DOI:10.1038/s41431-019-0508-0 diseases: analysis database. oftheOrphanet Eur EJHG. JHumGenet Lanneau V, etal. Estimating cumulative point prevalence ofrare Nguengang A,Rodwell C,Gueydan C, DM,Olry Wakap S,Lambert 59172018000100007&lng=es. www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S1728- Peruana. 2018 Jan;35(1):43–50. Disponible en: Disponible en: http:// JA. Factores enlasenfermedades deriesgo genéticas. Médica Acta Abarca H, Barriga Trubnykova M,Chávez Pastor J, M,LaSerna Poterico [email protected] Servicio deGenética delNiño, &EIM,Instituto NacionaldeSalud Av.Servicio Brasil 600,CPLima05,Lima,Perú. Self-financed. Hugo HernánAbarca Barriga. +51 979301132

The authorsdeclare that theyhave The authors participated The authorsparticipated properly certified properlyfor thesepurposes. certified professionals withinlaboratories andinstitutions out by and carried qualified and interdisciplinary the management ofalltheseconditions ismulti however,described; that itisofutmostimportance therapeutic optionsfor thesedifferent diseases therapies anddrugsare promising andvaluable Finally, to indicate that itisimportant allthese another level ofmedicine:Precision Medicine. understanding ofour"omics", itto thustaking mechanisms ofeachdisease, basedonanindividual to better andinherent understandtheunderlying The future ofmedicineingeneral isconditioned Approved: Received: of interestno conflicts in the publication of this article. 16. 16. 15. 14. 13. 12. 11. 10. 9. 2019]. Disponibleen:https://clinicaltrials.gov/ Home -ClinicalTrials.gov [Consultado [Internet]. del el16deoctubre Bioeng Biotechnol. 2018;6.DOI:10.3389/fbioe.2018.00130 European Advanced Therapy Products Medicinal andBeyond. Front Yu GuptaP,TTL, Ronfard V, Vertès AA,Bayon Y. Recent Progress in 018-0926-z Dis. JRare Orphanet 2018;13.DOI:https://doi.org/10.1186/s13023- inEurope: authorisation products methodological uncertainties. medicinal onorphan making regulatory-decision Evidence supporting Pontes C, Fontanet JM, Vives A, Gómez-Valent R, Sancho J, M, Ríos et al. 10.1002/ajmg.a.38326 rare geneticdisorders. A.2017;173(9):2307–22.DOI: Genet Am JMed Sun W, Zheng W, Simeonov and development A.Drug discovery for diseases/fda-orphan-drugs del2019].Disponibleen:https://rarediseases.info.nih.gov/octubre Center (GARD) –anNCATS Program [Consultado [Internet]. 15de List ofFDA DiseasesInformation andRare Drugs|Genetic Orphan 2018;1065:607–26. DOI:10.1007/978-3-319-77932-4_37 Approaches.Analysis, Adv andMachine-Learning Biol. ExpMed A,Bolón-Canedo Alonso-Betanzos V. Big-Data Analysis, Cluster org/10.1093/oxfordjournals.aje.a113137 periods. Am JEpidemiol. 1981,1;113(5):596–605.DOI:https://doi. application for sartwell’s ofincubation modelofthedistribution MJ. Age at onsetofgeneticdiseases:an Khoury HK, Armenian 2017;19(5):546–52. DOI:10.1038/gim.2016.143 J Am Genet. Med Coll Off Med Genet using apopulation-based cohort. of rareThe collective impact diseases in Western Australia: an estimate Walker CE, Mahede T, LJ, etal. GirschikJ, Davis G,Miller Brameld K, April 7,2020 April

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